
==== Front
Signal Transduct Target Ther
Signal Transduct Target Ther
Signal Transduction and Targeted Therapy
2095-9907
2059-3635
Nature Publishing Group UK London

1931
10.1038/s41392-024-01931-z
Review Article
Glucagon-like peptide-1 receptor: mechanisms and advances in therapy
Zheng Zhikai 12
Zong Yao 3
Ma Yiyang 12
http://orcid.org/0000-0002-5632-9118
Tian Yucheng 12
http://orcid.org/0000-0002-2286-1069
Pang Yidan 12
Zhang Changqing 12
Gao Junjie junjie.gao@shsmu.edu.cn

12
1 https://ror.org/0220qvk04 grid.16821.3c 0000 0004 0368 8293 Department of Orthopaedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233 China
2 https://ror.org/0220qvk04 grid.16821.3c 0000 0004 0368 8293 Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233 China
3 https://ror.org/047272k79 grid.1012.2 0000 0004 1936 7910 Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA 6009 Australia
18 9 2024
18 9 2024
2024
9 23418 2 2024
17 6 2024
16 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.

Subject terms

Metabolic disorders
Cell biology
https://doi.org/10.13039/501100001809 National Natural Science Foundation of China (National Science Foundation of China) 82002339 81820108020 82002339 81820108020 82002339 81820108020 82002339 81820108020 82002339 81820108020 82002339 81820108020 82002339 81820108020 Zheng Zhikai Zong Yao Ma Yiyang Tian Yucheng Pang Yidan Zhang Changqing Gao Junjie Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System (BJ1-9000-22-4002)issue-copyright-statement© West China Hospital, Sichuan University 2024
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pmcIntroduction

In recent years, GLP-1R and its agonists have garnered widespread attention in the medical community. GLP-1R, a core member of the GPCR family, is widely present on the surfaces of various cells in the human body.1,2 By specifically binding to the key hormone GLP-1, it regulates blood glucose levels and lipid metabolism.3,4 This receptor and its agonists hold significant therapeutic potential, reshaping the treatment approaches for multiple diseases, including diabetes, cardiovascular disorders, and neurodegenerative diseases.5–7 GLP-1 is a peptide produced by the cleavage of proglucagon, mainly synthesized in the intestinal mucosal L-cells, pancreatic islet α-cells, and neurons in the nucleus of the solitary tract.3,4 GLP-1RAs mimic the action of endogenous GLP-1, activating GLP-1R, thereby enhancing insulin secretion, inhibiting glucagon release, delaying gastric emptying, and reducing food intake through central appetite suppression.8–10 These mechanisms make GLP-1RAs powerful tools for controlling blood glucose and improving metabolic syndrome. Furthermore, their multifaceted mechanisms of action suggest potential applications beyond traditional metabolic disorders. From the discovery of the GLP-1 fragment GLP-1(7-37) to the development of more stable and long-acting GLP-1 analogs, these milestones represent significant breakthroughs in the medical field.11,12 For instance, the success of exenatide has not only spurred the development of potent GLP-1 analogs such as liraglutide and semaglutide but also unveiled the vast potential of GLP-1RAs in treating various systemic diseases. These developments underscore the importance of GLP-1RAs in modern therapeutics. The applications of GLP-1RAs extend far beyond diabetes management.5

Here we summarized the complex mechanisms of GLP-1RAs and their latest advancements in treating various diseases, such as musculoskeletal inflammation, obesity, cardiovascular diseases, NAFLD, neurodegenerative diseases, and various cancers. We introduce recent studies that demonstrate the remarkable performance of GLP-1RAs in slowing the progression of neurodegenerative diseases, reducing inflammation, and enhancing cardiovascular health. For example, in the treatment of Alzheimer’s diseases (AD) and Parkinson’s diseases (PD), GLP-1RAs have shown potential in slowing disease progression, while their anti-inflammatory properties offer new hope for conditions such as osteoarthritis (OA), rheumatoid arthritis (RA) and cardiovascular diseases.13–15 By integrating the latest clinical trial data, we explore the efficacy of GLP-1RAs in treating diseases of the nervous, cardiovascular, endocrine, and digestive systems. We show readers that GLP-1RAs have also been found to significantly reduce the risks of heart failure, atherosclerosis (AS), and hypertension, highlighting their broad therapeutic potential.16–19 As new indications continue to be developed, GLP-1 drugs demonstrate immense potential in the medical field, with future research expected to expand their therapeutic applications. The comprehensive exploration of their benefits underscores their transformative potential in medicine, positioning them as a promising approach for addressing a wide array of health issues and paving the way for new research and clinical applications.

The future of GLP-1RA therapy is promising. Researchers are developing more efficient formulations, such as long-acting and oral versions, to improve patient compliance and outcomes. With increasing clinical evidence, GLP-1RAs are set to become essential in treating complex and chronic diseases, offering significant health benefits and addressing unmet medical needs, thus enhancing patient quality of life and solidifying their role in future medical advancements.

Review of the history and milestones in GLP-1 research

In 1979, Richard Goodman found that anglerfish are an ideal source for pancreatic mRNA due to their concentrated cells. He extracted mRNA, spliced anglerfish DNA into bacteria, and used radioactive probes to find the somatostatin gene. In 1982, they published a paper in the Proceedings of the National Academy of Sciences (PNAS), revealing that the glucagon precursor gene actually encodes three peptides-glucagon and two new hormones expressed in the intestine.20 A year later, a research team led by Graeme Bell from Chiron Corporation published two papers in the journal Nature.21,22 They cloned and sequenced the preproglucagon gene, discovering GLP-1 and GLP-2 hormones. The focus shifted to GLP-1, with Svetlana Mojsov identifying its insulin-stimulating fragment, GLP-1(7-37), in 1983. This was inspired by prior GIP (glucose-dependent insulinotropic polypeptide) research, highlighting that besides GIP, other substances in the intestine also stimulate insulin secretion. This finding was later combined with research by Joel Habener and jointly published in JCI.11 The team of Jens Juul Holst at the University of Copenhagen in Denmark published a report in FEBS Letters, reaching the same conclusion in January 1987.23 In December 1987, Stephen Bloom’s team confirmed in a Lancet paper that GLP-1(7-36) is a human intestinal hormone that stimulates insulin production in the pancreas and lowers blood sugar.24 GLP-1, used for treating diabetes, is quickly broken down in the body, requiring high doses that can cause side effects like nausea. This led to the development of new drugs similar to GLP-1 but with a longer-lasting effect. John Eng marked a significant breakthrough; he isolated exendin-4, a peptide from the Gila monster’s venom, which is structurally similar to human GLP-1 but more stable. GLP-1 is degraded in the bloodstream in less than a minute, whereas this peptide, consisting of 39 amino acids, exendin-4, could last for more than two hours. This work was eventually published in the JBC journal in August 1991.25 In the early 1990s, despite John Eng’s team identifying a potential diabetes treatment in exendin-4, it initially lacked attention and funding for development. Eng personally secured a patent and partnered with Amylin, leading to the FDA-approved diabetes drug exenatide in 2005, the first GLP-1 analog. This sparked further advancements, including Novo Nordisk’s development of more potent analogs like liraglutide and semaglutide, with the latter achieving over $12 billion in sales by 2022. The journey began in the 1980s with research on Gila monster venom, culminating in the discovery of exendin-4, a stable, effective peptide for treating diabetes, demonstrating the progression from initial discovery to blockbuster diabetes medications. In July 2009, they published a paper in Nature Chemical Biology, reporting for the first time that dual agonists targeting GLP-1R and glucagon receptor (GCGR) had a better weight loss effect.26 This marked a significant advancement in obesity treatment research, especially in combining multiple drug targets. Matthias Tschöp and Richard DiMarchi developed the first dual and triple agonist weight loss drugs. Eli Lilly and Company is currently researching a dual agonist called tirzepatide, which has outperformed semaglutide in phase 3 clinical trials. Additionally, their under-development triple agonist, Retatrutide, has shown unprecedented weight loss effects in phase 2 clinical trials.16 Matthias Tschöp and his team discovered that dual agonists targeting both GLP-1 and GIP receptors (GIPR) are more effective in treating diabetes than those targeting only GLP-1R. These dual agonists were found to reduce blood sugar and increase insulin secretion in mice, monkeys, and humans.27 Subsequently, they investigated a triple agonist capable of simultaneously targeting the GLP-1R, the GCGR, and the GIPR. In December 2014, they published a paper in Nature Medicine, showing that the triple agonist’s weight loss effects in mice exceeded those of the dual agonists.28 (Fig. 1).Fig. 1 Growth and Timescale of Medical Publications on GLP-1 and GLP-1RAs. This figure illustrates the number of published articles over time, from 1978 to 2022, related to GLP-1 and GLP-1RAs, along with significant milestones in clinical trials. The data is visualized through three layered area graphs, each representing a different category of publications: research on GLP-1 (red area), GLP-1RAs (blue area), and clinical trials (green area). Key milestones are annotated on the timeline, including the identification of GLP-1 and GLP-2 through gene sequencing in 1983, the extraction of Exendin-4 from Gila monster venom in 1991, and the first FDA approval of a GLP-1 analog, Exenatide, in 2005. Liraglutide’s clinical trials began in 2000 and the drug’s FDA approval in 2010. Notable is the steep increase in the number of publications from 2000 onwards, reflecting a growing interest and development in the field. The peak in 2022 corresponds to GLP-1 drug sales hitting $22 billion, with the approval of semaglutide by the FDA in 2021 and the initiation of the first clinical trial for an oral diabetes drug based on GLP-1 in the same year. This graph underscores the expanding research and clinical importance of GLP-1-related therapies in the treatment of diabetes. The x-axis represents the year, ranging from 1978 to 2023, and the y-axis quantifies the number of published articles, with a scale ranging from 0 to 2500 articles annual. GLP-1RAs are artificial protein formulations that exhibit partial or complete amino acid sequence similarity to endogenous GLP-1 within the human body. These compounds possess enhanced stability, extended half-lives, and heightened biological potency, enabling them to mimic the actions of GLP-1. Ongoing advancements in research and development have resulted in the production of GLP-1RA with increasingly prolonged half-lives

GLP-1

GLP-1 is a peptide hormone generated through the enzymatic breakdown of proglucagon. It is synthesized in L-cells located in the intestinal mucosa, α-cells found in the pancreatic islet, and neurons residing in the nucleus of the solitary tract.29 GLP-1, an endocrine hormone, is secreted by enteroendocrine L-cells located in the distal jejunum, ileum, and colon in response to nutrient ingestion and neuroendocrine stimulation. It originates from the preproglucagon precursor, which undergoes enzymatic processing within intestinal L-cells, ultimately giving rise to GLP-1(1-37) and GLP-1(7-36) amide or GLP-1(7-37) peptide variants.30,31 GLP-1 is an incretin hormone that plays a pivotal role in the meticulous control of human blood glucose levels.32,33 Nevertheless, its duration of action is rather ephemeral, lasting a mere 1–2 min within the circulatory system under typical physiological conditions.34,35 Subsequently, GLP-1 undergoes enzymatic degradation facilitated by dipeptidyl peptidase IV (DPP-4), leading to the loss of its biological efficacy.36

GLP-1R

GLP-1R, a member of the GPCR family, exhibits specific affinity for GLP-1. It predominantly localizes to the cellular membrane of diverse cell types throughout the human body.37 Indeed, GLP-1R is present beyond the confines of the pancreas and extends to a multitude of organs and tissues throughout the body. Its extensive distribution and involvement in diverse physiological processes emphasize the important role of GLP-1R beyond the regulation of glucose metabolism.38–40 The phenotype observed after GLP-1R knockout (KO) includes various physiological and metabolic changes. GLP-1R plays a role in the central nervous system (CNS) regulation of appetite. GLP-1R KO can lead to increased appetite, contributing to weight gain.1 GLP-1R is involved in regulating both insulin and glucagon secretion, and its knockout can impair pancreatic function, thereby affecting the balance of these hormones and glucose homeostasis.41,42 GLP-1R is expressed in the cardiovascular system, and its knockout has implications for cardiovascular function.43,44 GLP-1R is present in the CNS, and its absence might contribute to alterations in behavior, mood, or cognitive function.45,46

GLP-1RAs

GLP-1RAs result from intricate structural modifications to GLP-1, enabling them to not only replicate the pharmacological functions of GLP-1 but also impede its hydrolysis by DPP-4, thereby extending the drug’s half-life.47,48 These synthetic protein preparations exhibit partial or complete amino acid sequence homology with endogenous GLP-1, rendering them resistant to degradation which resulting in a prolonged half-life and heightened biological activity.47,48 By emulating the biological activity of natural GLP-1, GLP-1RAs effectively fulfill the role of GLP-1, effectively lowering blood glucose levels without increasing the risk of hypoglycemia and demonstrating favorable safety profiles.49 GLP-1RAs represent a pharmacotherapeutic category of injectable hypoglycemic agents that are sanctioned as adjunctive therapies to diet and exercise for the management of type 2 diabetes mellitus (T2DM) in adult patients and potentially hold promise in addressing other medical conditions.7,50,51 As researchers dive deeper into their multifaceted properties, these medications exhibit the potential to offer therapeutic benefits across a spectrum of diseases in human populations.

The development of GLP-1RAs

The Gila monster, which lives in the deserts of the Americas, can eat up to half its own body weight in one sitting, but its blood sugar remains stable, and its metabolic system runs smoothly despite this large amount of food.52,53 In 1992, Dr. John Enn discovered an exopeptide in the saliva of the Gila monster which he named exendin-4. Dr. John found that exenatide is an analog of human GLP-1RA, with 53% homology to human GLP-1RA; exenatide can stimulate human insulin secretion and regulate blood glucose levels in the body. This hormone is not readily degraded by DPP-4 to GLP-1 in the human body and can act for 12 h or longer.25

In 2005, exenatide was approved by the U.S. Food and Drug Administration (FDA) for use in treating T2DM;52 thus began the competition between various GLP-1RAs. GLP-1RAs are being developed to be more similar to the natural GLP-1 hormone found in the human body. This is achieved by replacing and modifying specific amino acids in human GLP-1.54,55 By doing so, the resulting product has a higher similarity or homology to the amino acid sequence of human GLP-1. In addition, efforts are being made to extend the duration of action of GLP-1RAs. Currently, some GLP-1RAs require daily injections, which can be inconvenient for patients. Therefore, researchers are working toward developing formulations that can be administered once a week, providing a longer-lasting effect and reducing the frequency of injections.56,57 Furthermore, there is a focus on developing GLP-1RAs that can be taken orally without the need for injections. This oral preparation would offer a more convenient and comfortable option for patients, potentially leading to better treatment compliance.58,59 Overall, the future research direction of GLP-1RAs involves making them more similar to those in the human body, extending their duration of action, and creating oral formulations for easier administration.60,61 These advancements aim to improve patient experience, compliance, and treatment outcomes.

Exenatide is the world’s first GLP-RA product; it was developed in 1995 and approved for marketing in 2005.60 Liraglutide was subsequently approved for marketing in February 2010,62 and lixisenatide was approved for marketing in the European Union in 2013 for the treatment of T2DM and in the United States in July 2016.63 Albiglutide was approved for marketing in the European Union in March 2014 and in the United States in April 2014.64 Dulaglutide was approved for marketing in the U.S. in September 2014 for the treatment of T2DM65; semaglutide was approved for marketing in the United States in September 201766; and beinaglutide is a GLP-RA product developed by a Chinese company and was approved for marketing for the treatment of T2DM in China in September 2016.67 PEG-loxenatide, China’s first long-acting GLP-RA product, was approved for marketing in China in May 2019.66 (Tables 1 and 2)Table 1 Comparison of GLP-1RAs used in type 2 diabetes mellitus

Date	Brand name	GLP-1RA	Half-life	Dose (SC)	Molecular formula	Clinial trial focus	
2005	Byetta	Exenatide	2.4 h	5 μg or 10 μg b.i.d sc	C149H234N40O47S	Parkinson disease	
2010	Victoza/Saxenda	Liraglutide	11-13 h	0.6 mg and 1.2 or 1.8 mg q.d sc	C172H265N43O51	Cardiovascular disease	
2013	Adlyxin (U.S)/Lyxumia (EU)	Lixisenatide	2–4 h	10 μg then 20 μg q.d sc	C215H347N61O65S	Early Parkinson disease	
2014	Tanzeum	Albiglutide	6-8 h	30 or 50 mg q.w sc	C148H224N40O45	Cardiovascular disease	
2014	Trulicity	Dulaglutide	108-112 h	0.75 or 1.5 mg q.w sc	C2646H4044N704O836S18	Type 2 diabetes	
2017	BYDUREON BCise	Exenatide (ER)	2 w	2 mg q.w sc	C184H282N50O60S	Type 1 diabetes	
2017	Ozempic	Semaglutide	6-7 d	0.25 mg then 0.5 mg q.w sc	C187H291N45O59	obesity-related heart failure	
2019	Rybelsus	Oral Semaglutide	24 h	3 mg then 7 mg q.d po	C187H291N45O59	Type 2 diabetes	
Form: Pen, SC injection; po, orally

q.d once daily, q.w once weekly, b.i.d twice daily, t.i.d three times daily, SC subcutaneous administration, w week, po orally

Date: Refers to the date when the drug was approved by the U.S. Food and Drug Administration (FDA)

Clinical Trial Focus: Describes the main diseases targeted in recent clinical trials

Table 2 Comparative overview of efficacy and adverse effects of mainstream GLP-1RA medications

	CV benefit	Renal benefit	Weight loss	Patient adherence	HbA1c reduction	HbA1c problem	Injection reactions	GI side effects	Antibody issues	
Exenatide					+	−−	−−	−	−−	
Lixisenatide					+	−−	−−	−	−	
Oral Semaglutide	++				+	−−		−−		
Dulaglutide	++	+		++	++	−−−				
Liraglutide		+	++	++	++	−−		−−		
Exenatide (ER)				++	++	−			−	
Semaglutide (S.C)	+++	+++	+++	++	++			−		
CV cardiovascular, GI gastrointestinal, RE extended-release, SC subcutaneous administration

The “+“ and “−“ symbols indicate the efficacy profile or adverse effect profile of each parameter, with more symbols meaning greater strength or severity. More “+“ signs indicate a greater benefit. More “−“ signs indicate more severe side effect issues

Current GLP-1RAs

GLP-1RAs are synthetic protein preparations that have partial or complete amino acid sequence homology with GLP-1 found in the body, are not easily degraded, have longer half-lives and have stronger biological activity. They can play the role of GLP-1.49 GLP-1RA is primarily used for the treatment of T2DM68 and works by mimicking the action of the naturally occurring hormone GLP-1, which is released by the intestines in response to food intake. GLP-1 helps regulate blood sugar levels by stimulating the release of insulin, suppressing glucagon secretion (which raises blood sugar levels), and slowing the rate at which the stomach empties, leading to a feeling of fullness and reduced appetite.69 In addition to its use in diabetes management, GLP-1RA has also shown potential in other areas of research. Studies have explored its effects on weight loss, NAFLD,70 and neurodegenerative diseases such as AD.71 Furthermore, GLP-1RA has been investigated for its potential to reduce the risk of cardiovascular events in patients with or without diabetes.5,19 Like any medication, GLP-1RAs may have side effects, including nausea, vomiting, diarrhea, and injection site reactions. These side effects are often mild and tend to improve over time.72–74 Rare but serious side effects may include pancreatitis and allergic reactions.75

Exenatide

Exenatide is a medication that belongs to the class of drugs known as GLP-1RAs. It is a synthetic version of the hormone exendin-4, which is found in the saliva of the Gila monster, a venomous lizard native to the southwestern United States.76 Exenatide is composed of 39 amino acids and shares 53% sequence identity to human GLP-1. The second position of its N-terminus is glycine (alanine in GLP-1), which is not easily degraded by the DPP-4 enzyme.77 Compared with GLP-1, the C-terminus of its amino acid sequence contains 9 additional amino acid residues (PSSGAPPPS), which are not easily degraded by peptide chain endonucleases; thus, it has a long half-life and strong biological activity.78 The average half-life of exenatide is 2.4 h, 2 to 3 times per day.78

Liraglutide

Liraglutide is a medication used to treat T2DM and obesity.79,80 In the treatment of T2DM, liraglutide helps lower blood sugar levels by increasing insulin production and reducing glucose production by the liver.81 It also slows stomach emptying, which helps control appetite and reduce food intake.82,83 In addition to lowering blood sugar levels, liraglutide helps to reduce body weight by suppressing appetite and reducing energy intake,84,85 but its associated costs and need for daily injections may limit its use in individuals with obesity.86–88 Liraglutide was first approved by the FDA in 2010 under the brand name Victoza for the treatment of T2DM.83,89–92 Since then, it has also been approved for other indications, such as chronic weight management, under the brand name Saxenda.62 Liraglutide has an arginine at position 34 (GLP-1(7-37)) that is lysine, and its lysine at position 26 connects to a 16-carbon palmitic acid side chain linked by glutamic acid. Liraglutide shares 97% sequence homology with human GLP-1 and can bind to and activate GLP-1R.78 The elimination half-life of liraglutide is 13 h, and only one injection per day is required.62

Lixisenatide

Lixisenatide was developed by Sanofi to treat T2DM.64,93 Structurally, lixisenatide is based on the exenatide structure but lacks proline at position 38, and six lysines are linked after serine at position 39.94 The six lysine residues increase the rigidity of the molecule’s structure, thus allowing its drug properties to be improved.78 These changes stabilize its structure, prevent protein degradation of the molecule in the circulation, and increase the circulation time enough to ensure once-daily injection (compared with exenatide, which is injected two or three times daily). The average half-life of lixisenatide is approximately 3–4 h.95 Lixisenatide is a short-acting GLP-1RA agent,96,97 and once-daily lixisenatide can improve patient compliance to a certain extent and reduce the occurrence of hypoglycemia.98–100 The injection is usually given within one hour before the first meal of the day, preferably at the same time each day. It is important to avoid injecting lixisenatide after a meal or in case of a missed meal. The initial recommended dosage of lixisenatide is 10 mcg once daily for at least 14 days. After the initial period, its dosage may be increased to 20 mcg once daily if additional glycemic control is needed. The maximum recommended dosage is 20 mcg once daily.101

Albiglutide

Albiglutide was approved by the FDA in 2014. As a GLP-1RA,102 albiglutide works by stimulating insulin release and reducing glucagon production, leading to improved blood sugar control in patients with T2DM.102,103 Albiglutide is a long-acting GLP-1RA injected subcutaneously once a week. The half-life of albiglutide is approximately 4 to 7 days.102 Compared with the structure of human GLP-1(7-36), the amino acid sequence of albiglutide contains an arginine at position 8 (in GLP-1, this residue is lysine), and two modified GLP-1 peptide chains are fused to human serum albumin (HSA), thereby greatly extending its half-life.104,105 Albiglutide is typically prescribed in combination with diet and exercise. The dosage of albiglutide is usually 30 mg once a week. It is administered as a subcutaneous injection (just under the skin). The injection site can be the thigh, abdomen, or upper arm.102

The FDA set several usage restrictions upon the initial approval of Tanzeum (albiglutide), reflecting considerations of suitability and safety for specific patient groups. Firstly, Tanzeum is not recommended as a first-line treatment for patients inadequately controlled with diet and exercise.49 Secondly, its safety and efficacy remain unclear in patients with a history of pancreatitis as it has not been studied in this group.106 Additionally, Tanzeum is not suitable for treating type 1 diabetes or diabetic ketoacidosis, related to its pharmacological action and target disease. It is also not recommended for patients with existing gastrointestinal disease to avoid potential side effects or exacerbating the condition.107 Further, serious risks associated with Tanzeum use include pancreatitis, acute kidney injury, renal impairment, and pneumonia, further limiting its use in specific conditions or susceptible patients. These restrictions and warnings demonstrate the FDA’s stringent consideration of patient safety in the drug approval process.108 In March 2015, the FDA required a black box warning on Tanzeum due to the observed risk of thyroid C-cell tumors in animals, although it is unclear if this effect also occurs in humans.108 Later, the FDA added a warning about the risk of anaphylactic shock to the medication’s label. This reaction is severe and potentially life-threatening, including symptoms like unease, tingling, dizziness, itching, hives, swelling, difficulty breathing, and fainting.81,107,109

Tanzeum was discontinued by GlaxoSmithKline (GSK) in 2017, primarily due to economic factors.110,111 Despite GSK’s attempts to gain a competitive edge through low pricing, Tanzeum failed to achieve sufficient market acceptance.106 In 2017, Tanzeum was removed from the preferred drug list of leading pharmacy benefit manager (PBM) company Express Scripts and was replaced by Eli Lilly’s Trulicity, highlighting Tanzeum’s weak market presence.106,108 Moreover, this decision was part of a broad strategic reform led by GSK’s new CEO Emma Walmsley.106 This reform aimed to refocus the company’s efforts on areas with higher revenue potential, such as respiratory and HIV treatments, as well as oncology and immunology.108 Additionally, Tanzeum struggled to establish a significant market share in the competitive GLP-1RA market, which was another reason GSK decided to withdraw the drug globally.108

Dulaglutide

Dulaglutide was approved by the FDA in 2014 for the treatment of T2DM.112 Dulaglutide is a once-weekly long-acting GLP-1RA. Compared with the structure of human GLP-1(7-37), the amino acid sequence of dulaglutide contains glycine at position 8, glutamic acid at position 22, and glycine at position 36.113 It was then fused to the constant region (Fc) of modified human immunoglobulin G4 (IgG4) via a “-(Gly-Gly-Gly-Gly-Ser) 3-Ala-“ bridge and exhibits an average biological half-life of 90 h.105 Dulaglutide is the first large-molecule GLP-1RA, and the weekly dosing frequency of dulaglutide can greatly improve patient compliance.33,78,104,114

Semaglutide

Semaglutide is a long-acting GLP-1RA agent used once weekly to improve glycemic control in patients with T2DM.115 Compared with the structure of human GLP-1(7-37), the amino acid sequence of semaglutide contains diaminoisobutyric acid at position 8, arginine at position 34, and acylated lysine at position 26.31 Semaglutide has a longer aliphatic chain and increased hydrophobicity, but its hydrophilicity is greatly enhanced by PEG modification of the short chain. Modified DPP-4 can not only mask the enzymatic hydrolysis site of DPP-4 but also bind closely with albumin to reduce renal excretion and prolong the half-life.35,104,116 On August 22, 2022, Novo Nordisk announced the primary results of the Phase II clinical trial for the dual-action compound CagriSema, which demonstrated effective blood sugar reduction and weight loss. CagriSema is composed of the GLP-1 RA semaglutide and the long-acting insulin analog cagrilintide, and can be administered subcutaneously once a week.117

Beinaglutide

Beinaglutide was the first original drug approved for the treatment of obesity in China and the third GLP-1 class reduction drug approved worldwide, and it represents a new treatment option for overweight and obese patients.67,118,119 Beinaglutide, a recombinant human GLP-1 (rhGLP-1) polypeptide, exhibits a remarkable resemblance to human GLP-1(7-36), with nearly 100% homology.120 This innovative compound demonstrates dose-dependent efficacy in regulating glycemic control, suppressing appetite, delaying gastric emptying, and facilitating weight reduction.121 Consequently, beinaglutide holds significant promise for advancing research in the areas of overweight/obesity and nonalcoholic steatohepatitis (NASH).67,122 Beinaglutide is a natural human GLP-1(7-36)-NH2 expressed in Escherichia coli. This product was approved for the treatment of T2DM; it has a half-life of 11 minutes and requires 3 injections per day.78

Polyethylene glycol liraglutide

Polyethylene glycol liraglutide (PEG-loxenatide) is a long-acting GLP-1RA. It was the world’s first PEGylated long-acting GLP-1RA.123 PEG-loxenatide is used for blood glucose control in adult patients with T2DM. Structurally, the product was optimized on the basis of exenatide, and the glycine 2, methionine 14 and asparagine 28 positions were modified to improve enzyme stability and chemical stability based on the polypeptide backbone. Moreover, the C-terminal serine of the peptide was replaced by cysteine via site-directed mutagenesis performed with polyethylene glycol.78 The half-life of PEG-loxenatide is approximately 1 week.123

Multi agonists

In recent years, the development of dual and triple agonists related to GLP-1 has been vigorously pursued.124–126 The design concept of these multi-agonists is to simultaneously regulate multiple key metabolic pathways to achieve more effective control over blood sugar, body weight, and overall metabolic health.43 Currently, these drugs are primarily in the development and clinical trial stages, but preliminary research results have shown their potential powerful effects in reducing blood sugar and body weight.127,128

Dual agonists

Dual agonists target both the GLP-1R and another specific receptor.124,129 A common combination is GLP-1 with GIP or insulin-like growth factor.130 For example, a popular dual agonist, tirzepatide (brand name Mounjaro), activates both GLP-1 and GIPR.124 GLP-1, by activating its receptor, increases insulin secretion and reduces glucagon secretion, thereby lowering blood sugar levels.131–133 Additionally, GLP-1 helps to delay gastric emptying and suppress appetite, aiding in weight management.121,134 GIP, another insulin secretion agonist, helps release insulin, particularly after eating, enhancing the effects of GLP-1 and thereby improving the overall therapeutic efficacy of the drug.125,130 In 2022, tirzepatide was approved by the FDA for the treatment of T2DM in the United States.135,136 It is considered a significant breakthrough in diabetes treatment and is also being studied for the treatment of obesity due to its significant weight loss effects.135 Tirzepatide is developed by Eli Lilly and has proven to provide superior blood sugar control and significant weight loss, making it particularly valuable in the treatment of T2DM.136–138 Research and clinical trials have shown that tirzepatide not only improves blood sugar levels but also has a positive impact on cardiovascular risk factors.139–141 Although dual agonists show advantages in efficacy, their safety and tolerability continue to be a focus of ongoing monitoring.141 Common side effects include gastrointestinal reactions, such as nausea and vomiting, which are typically more common during the initial stages of treatment.141,142 The Phase III clinical trials of tirzepatide were conducted in 77 research centers across seven countries, including the United States, Brazil, and Japan.143 The trials recruited adult participants with T2DM and significantly reduced body weight and improved blood sugar control in these patients.143 The safety profile of tirzepatide is similar to other drugs in its class, providing an effective new treatment option for patients with T2DM and obesity. Current dual agonists under investigation also include efinopegdutide and cotadutide.144–147

Triple agonist

Triple agonists go even further.148 These drugs act by simultaneously targeting three different agonists GLP-1R, the GIPR, and the GCGR.149–151 These receptors each have independent yet complementary roles in the treatment of diabetes and obesity.150,152,153 Activation of the GLP-1R can enhance insulin secretion, reduce glucagon secretion, delay gastric emptying,154 and suppress appetite.155,156 GIPR activation also promotes insulin release, especially after meals, helping to improve glucose utilization.157,158 Activation of the insulin or Insulin-like Growth Factor 1 (IGF-1) receptor can enhance insulin sensitivity, improve glucose absorption and utilization by cells, and potentially have positive effects on cardiovascular health and long-term energy balance.159 As of now, GLP-1-related triple agonists are primarily still in the development stage and have not been widely approved for use.159 These drugs are not yet widely available on the market but have shown some potential in clinical trials.160,161 For example, HM15211, a triple agonist developed by Hanmi Pharmaceutical in South Korea that activates GLP-1R, GIPR and GCGR has entered early clinical trials for the treatment of obesity and non-alcoholic steatohepatitis (NASH).162,163 Retatrutide (LY-3437943), a novel triple agonist developed by Eli Lilly that targets GLP-1R, GIPR and GCGR, has shown potential in preliminary clinical data for providing excellent blood sugar control and significant weight reduction.158,161,164,165 However, activating multiple receptors may lead to more complex side effects, and in some experiments, dual and triple agonists have indeed shown more severe side effects.165,166 Retatrutide has now entered Phase III clinical trials.161 The results of the Phase II clinical trials of retatrutide were published in The Lancet in 2023.161 The trials involved adult participants with T2DM aged 18 to 75, conducted across 42 research and medical centers in the United States.161 Over a period of 24 weeks, all dosage groups of retatrutide showed significant improvements in reducing glycated hemoglobin (HbA1c) and body weight compared to the placebo group, especially in the higher dosage groups. In terms of safety and tolerability, the adverse events were primarily mild to moderate gastrointestinal reactions, with no reports of severe hypoglycemia or death.161

In summary, dual and triple agonists related to GLP-1 represent significant advances in the field of diabetes treatment,167,168 demonstrating the future trend of enhancing therapeutic effects by targeting multiple biomarkers.136,169,170 With the accumulation of more clinical data and the development of new drugs, these treatment options are expected to provide more effective and comprehensive treatment choices for diabetes patients.161,167

Small molecule GLP-1RAs

Currently, most GLP-1RAs are based on proteins or peptides, meaning they are large molecules typically administered via injection.37 Small molecule GLP-1RAs are chemically synthesized, and compared to protein-based drugs, they generally have smaller molecular sizes.171 The development of small molecule GLP-1RAs aims to overcome some of the limitations of traditional protein or peptide-based GLP-1RAs, such as the need for injection. Small molecule drugs may offer the possibility of oral administration, which is more convenient and acceptable for patients.171 Additionally, small molecule drugs may have better tissue permeability, longer half-lives in the body, and lower production costs. As of now, research on small molecule GLP-1RAs is still mainly in the laboratory and early clinical trial stages.172 The challenges in developing these drugs include ensuring that they can effectively mimic the biological activity of large molecule GLP-1RAs while maintaining efficacy and selectivity. This review article will introduce some of the small molecule drugs that are currently receiving significant attention:

Orforglipron

Orforglipron is an oral small molecule GLP-1RA developed jointly by Eli Lilly and Chia Tai Tianqing Pharmaceutical Group.173 Its research findings were recently presented orally at the 83rd Scientific Sessions of the American Diabetes Association and published in the New England Journal of Medicine. In a 26-week study, orforglipron demonstrated a significant dose-dependent effect on weight loss, with weight reduction ranging from 8.6% to 12.6% across various dosages, compared to only 2.0% in the placebo group. By week 36, this weight loss effect was even more pronounced, increasing from 9.4% to 14.7%, while the placebo group saw a reduction of only 2.3%. Additionally, in another Phase II study targeting patients with T2DM, orforglipron also showed significant effects in reducing A1C and weight, achieving the study’s primary and secondary endpoints. In this study, participants taking orforglipron experienced an average A1C reduction of 2.1% and an average weight loss of 10.1 kilograms at 26 weeks, which was significantly greater than those in the placebo and dulaglutide groups. Between 65% and 96% of participants taking orforglipron achieved an A1C level below 7.0% at 26 weeks.174 Currently, Eli Lilly has initiated a Phase III development program to further investigate the efficacy and safety of orforglipron in treating obesity, overweight, and T2DM.

Danuglipron

Danuglipron is an oral GLP-1RA developed by Pfizer. In May 2023, Pfizer released the results of a Phase 2b clinical trial of the drug. The study involved 411 adult patients with T2DM and was designed as a randomized, double-blind, placebo-controlled trial where patients received varying doses of danuglipron or a placebo. The results showed that during the 16-week treatment period, patients who received the highest dosage (120 mg twice daily) of danuglipron experienced an average reduction in HbA1c of 1.16 percentage points and a weight loss of 4.17 kilograms. All dosages of danuglipron significantly reduced patients’ HbA1c and fasting blood glucose levels, with more pronounced weight loss effects observed in the 80 mg and 120 mg doses compared to the placebo group. Common adverse reactions included nausea, diarrhea, and vomiting.172

GSBR-1290

GSBR-1290 is an oral small molecule GLP-1RA developed by Structure Therapeutics, aimed at treating T2DM and obesity. On December 18, 2023, Structure Therapeutics published the latest clinical data for GSBR-1290 on its official website.175 Currently, GSBR-1290 is undergoing a 12-week Phase 2a randomized, double-blind, placebo-controlled clinical trial to assess its effectiveness in treating patients with T2DM and obesity. To date, the trial has enrolled 94 participants, with 54 in the T2DM group and 40 in the obesity group. Regarding safety, the majority of reported adverse events were mild to moderate, ranging from 88% to 96%, depending on the specific study group. Among the 60 participants treated with GSBR-1290, only one (2.8%, from the T2DM group) discontinued the study due to drug-related adverse events (AEs). As for clinical outcomes, in the T2DM group, there was a significant reduction in HbA1c (decreased by 1.01% to 1.02%, placebo-adjusted) and a clinically meaningful decrease in body weight of 3.26% to 3.51% after 12 weeks of treatment. In the obesity group, there was a significant and clinically meaningful reduction in body weight of 4.74% at week 8, with weight continuously decreasing during the 8-week treatment period.175

Classical pathophysiological mechanisms of GLP-1

GLP-1 signaling pathway

GLP-1 initiates signaling by binding to its receptor, GLP-1R, which is a G-protein-coupled receptor.176,177 When GLP-1 binds to GLP-1R, it triggers the activation of G-proteins, leading to an increase in the intracellular second messenger cAMP.34,39,177 The rise in cAMP activates protein kinase A (PKA), which then promotes the synthesis and secretion of insulin and inhibits the release of glucagon.178,179 Additionally, cAMP can activate Rap1 through EPAC (Exchange Protein directly Activated by cAMP),180–182 which is involved in regulating insulin secretion.180,181,183 GLP-1 also activates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, which is crucial for maintaining the survival and function of pancreatic β-cells.184–187

Interactions with other pathways

GLP-1 not only promotes the release of insulin but also enhances the response of pancreatic β-cells to insulin through the PI3K/Akt pathway, thereby improving insulin signal transduction and increasing the sensitivity of peripheral tissues to insulin.1,188 GLP-1 reduces hepatic glucose production, partly by inhibiting the expression and activity of key gluconeogenic enzymes.189–191 Activation of GLP-1R leads to the production of cAMP (cyclic Adenosine Monophosphate), which is achieved by activating Adenylyl Cyclase (AC).191,192 Following the activation of GLP-1R, the βγ subunits of GPCRs can directly activate Class I PI3Ks.1 These PI3Ks typically include the PI3Kα and PI3Kβ isoforms, which are composed of regulatory subunits containing SH2 domains and catalytic subunits.193 These subunits can directly interact with the activated GPCR or do so via intermediary proteins such as insulin receptor substrate.194,195 The activated PI3K catalyzes the conversion of membrane phospholipid Phosphatidylinositol-4,5-bisphosphate (PIP2) into Phosphatidylinositol-3,4,5-trisphosphate (PIP3).196 The generation of PIP3 is a crucial step for the activation of Akt, as PIP3 provides a membrane docking site for Akt, facilitating its translocation to the cell membrane.197 Akt, also known as Protein Kinase B (PKB), once positioned at the membrane, can be phosphorylated by PIP3-dependent kinase 1 (PDK1) and possibly PDK2 (such as mTORC2).196–198 The phosphorylation of Akt is necessary for its full activation, allowing it to regulate a variety of downstream effector proteins involved in cell survival, proliferation, metabolism, and glucose transport.199 Activated Akt promotes the expression and translocation of GLUT4 (Glucose Transporter Type 4) to the cell membrane, increasing cellular glucose uptake.200–202 Simultaneously, Akt promotes cell survival by phosphorylating and inhibiting a series of pro-apoptotic proteins, such as Bad and the FOXO family.202–204 Moreover, Akt can activate mTORC1, further promoting cell growth and protein synthesis. Through these molecular mechanisms, GLP-1 not only plays a crucial role in the treatment of diabetes by enhancing the function and protecting pancreatic β-cells from apoptosis, but it may also offer potential therapeutic benefits in fields such as cardiovascular and neural protection.198,205,206 GLP-1 can also enhance the uptake and utilization of glucose in muscle and adipose tissues.207–209 And GLP-1’s action in the brain reduces appetite and may influence energy expenditure.176,210,211 These effects involve interactions with other satiety and hunger signals, such as PYY, CCK, insulin, and leptin.212,213

The pathophysiological mechanism of GLP-1 in metabolic diseases

GLP-1 plays a crucial role in the pathophysiology of metabolic diseases, particularly in T2DM and obesity.213–215

Role of GLP-1 in T2DM

GLP-1 significantly influences the functionality of pancreatic β-cells and α-cells, contributing to its therapeutic effect on T2DM.132,216,217 As a vital incretin hormone, GLP-1 enhances glucose-dependent insulin secretion.3 It also promotes proliferation and reduces apoptosis of pancreatic β-cells, thereby maintaining their quality and functionality.130,218 At the molecular level, GLP-1 activates the cAMP response element-binding protein (CREB) via its receptor (GLP-1R), a transcription factor crucial for expressing the insulin gene.3,130,219 GLP-1 also activates PKA and EPAC through a cAMP-dependent pathway.1,220 PKA, a key enzyme, phosphorylates various target proteins, affecting their activity and function, which in turn promotes insulin synthesis and secretion.178,180 The PI3K/Akt signaling pathway, activated by GLP-1, plays a vital role in maintaining pancreatic β-cell survival and promoting their proliferation.221,222 Activation of Akt stimulates β-cell proliferation, reduces apoptosis, and enhances insulin secretion by regulating downstream effector molecules like Forkhead box protein O1 (FoxO1) and the glucose transporter type 2 (GLUT2).223,224

GLP-1 also inhibits glucagon release from α-cells, which is beneficial for reducing blood glucose levels since glucagon promotes hepatic gluconeogenesis.131,225 GLP-1’s action on α-cells regulates glucagon release.131 The direct impact of GLP-1 on these cells slows the secretion of glucagon, essential for maintaining glucose stability, especially postprandially.131,226 When GLP-1 binds to its receptor on α-cells, it activates intracellular cAMP production.227 In α-cells, increased cAMP affects glucagon synthesis and release.228 PKA, activated by cAMP, can regulate the activity of K-ATP channels in α-cells.228,229 The opening of these channels is controlled by the intracellular ATP/ADP ratio.229 Specifically, PKA modifies the open state of K-ATP channels through phosphorylation, affecting the cell membrane’s potential and intracellular calcium ion concentration.230,231 By modulating the activity of K-ATP channels, GLP-1 indirectly controls the calcium signaling in α-cells, thereby influencing glucagon secretion.232,233 GLP-1 inhibits the release of glucagon from α-cells through multiple mechanisms. GLP-1 can directly bind to the receptors on the surface of α-cells in the pancreas, inhibiting the secretion of glucagon from these cells.234,235 Glucagon is a hormone secreted by pancreatic α-cells that stimulates the liver to release glucose. Therefore, inhibiting the release of glucagon is crucial when blood glucose levels need to be lowered. GLP-1 can stimulate pancreatic β-cells to release insulin.236,237 Insulin not only directly lowers blood glucose levels but also further inhibits glucagon secretion from α-cells through a feedback mechanism.238 The high concentration of insulin in the local pancreatic environment creates a negative feedback effect, reducing the amount of glucagon secreted by α-cells.234 Additionally, GLP-1 can reduce blood glucose production by delaying gastric emptying and decreasing appetite, which also contributes to overall blood glucose control.239,240 In summary, GLP-1 lowers blood glucose levels and inhibits glucagon secretion through direct action on α-cells, promotion of insulin secretion, and regulation of gastrointestinal activity.241

GLP-1R is expressed not only on β-cells and α-cells but also on δ-cells in the pancreatic islets.242 δ-cells primarily secrete somatostatin, which is an important regulatory hormone.242 The expression of GLP-1R on δ-cells helps to inhibit the secretion of glucagon.242 When GLP-1 binds to GLP-1R on δ-cells, it activates these cells and promotes the secretion of somatostatin.243 Somatostatin is a potent inhibitory hormone that affects the surrounding α-cells and β-cells. It acts directly on neighboring α-cells to inhibit the secretion of glucagon and can also indirectly influence α-cells by inhibiting the secretion of other hormones.243 In the local islet environment, a high concentration of somatostatin creates an inhibitory milieu, further reducing the activity of α-cells and the secretion of glucagon.244 Additionally, somatostatin can inhibit gastrointestinal activity, reducing the secretion of pancreatic enzymes and gastric acid, thereby indirectly decreasing the demand for glucagon.245,246 Hence, GLP-1 activates δ-cells and promotes somatostatin secretion, forming a multi-layered inhibitory mechanism that effectively reduces glucagon secretion.

The relative expression levels of GLP-1R on α-cells and δ-cells exhibit certain differences. These variations significantly influence the role of GLP-1 in regulating islet function and glucose homeostasis.131 Research indicates that the expression level of GLP-1R on α-cells is relatively low.131 Although GLP-1Rs are present, they are limited in number, making the direct inhibitory effect of GLP-1 on α-cells relatively weak.247 The primary action often occurs through indirect mechanisms, such as insulin and somatostatin.244 Conversely, the expression level of GLP-1R on δ-cells is relatively high.248 GLP-1 can effectively bind to receptors on δ-cells, stimulating the secretion of somatostatin.248 As a broad-spectrum inhibitory hormone, somatostatin can effectively inhibit glucagon secretion from α-cells and insulin secretion from β-cells.249,250 Relevant studies suggest that the expression of GLP-1R on δ-cells is crucial for GLP-1’s regulation of somatostatin secretion and the overall inhibitory effect on glucagon.248,251,252 This mechanism is particularly evident in the use of GLP-1-based drugs, such as GLP-1RAs, in the treatment of T2DM. In summary, the relatively higher expression of GLP-1R on δ-cells allows GLP-1 to indirectly inhibit glucagon secretion by promoting somatostatin secretion. In contrast, the lower expression of GLP-1R on α-cells results in a limited direct effect. Although these three types of cells each have distinct functions, it is more important to note that the somatostatin, glucagon, and insulin they secrete work together through mutual regulation and feedback mechanisms to maintain blood glucose balance and overall metabolic homeostasis.253,254

GLP-1 usually refers to GLP-1(7-36), a peptide chain consisting of 36 amino acids and the primary active molecule.255 GLP-1(7-36) stimulates the release of paracrine glucagon inhibitory factors by activating GLP-1R on β-cells and δ-cells.241 DPP-4 cleaves GLP-1(7-36) at the 8th position, generating GLP-1(9–36). GLP-1(9–36) is the product of GLP-1(7-36) degradation by DPP-4, and this process rapidly reduces the activity of GLP-1(7-36).35,256,257 Traditionally, GLP-1(9–36) was considered a metabolically inactive product of GLP-1, losing its primary function of regulating blood sugar.258 However, increasing research suggests that GLP-1(9–36) may have other physiological roles. Recent studies show that GLP-1(9–36) can activate the inhibitory G protein (Gi/o), leading to the translocation of secretory granules (SG) beneath the cell membrane, thereby inhibiting glucagon secretion.241 This mechanism is unaffected by genetic or pharmaceutical inhibition of GLP-1R, but it is sensitive to pertussis toxin. As exendin-4 is more resistant to DPP-4-induced degradation, this mechanism is not activated by exendin-4.241 GLP-1(9–36) can directly act on pancreatic α-cells to inhibit the secretion of glucagon. Recent studies have shown that GLP-1(9–36) is particularly effective at low glucose concentrations, with its inhibitory effect being similar to that of GLP-1(7-36).241 GLP-1(9–36) retains its ability to inhibit glucagon secretion even after GLP-1R inactivation, suggesting that its mechanism of action may not be entirely dependent on the GLP-1R.241 GLP-1(9–36) promotes the undocking of secretory granules (SG) by inhibiting the entry of Ca2+ through voltage-gated Ca2+ channels. As a result, GLP-1(9–36) reduces the number of granules available for exocytosis in α-cells, thereby decreasing the release of glucagon.241 This mechanism decreases intracellular Ca2+ concentration, thereby inhibiting glucagon secretion.241 Additionally, GLP-1(9–36) can effectively inhibit glucagon secretion induced by β-adrenergic stimulation, amino acids, and membrane depolarization, indicating its inhibitory effect under various stimulatory conditions.241 In α-cells of patients with T2DM, the ability of GLP-1(9–36) to inhibit glucagon secretion is lost. This may be due to altered α-cell function in diabetic patients, which impairs the efficacy of GLP-1(9–36).241 In vivo experiments have shown that high concentrations of exogenous GLP-1(9–36) can lower circulating glucagon levels during insulin-induced hypoglycemia. However, this effect is significantly diminished or absent in diabetes.241 As a degradation product of GLP-1(7-36), GLP-1(9–36) has a notable inhibitory effect on glucagon secretion, demonstrated in both in vitro and in vivo studies. However, this inhibitory effect is significantly weakened in patients with T2DM, indicating that its potential application in diabetes treatment requires further investigation.241 Through this series of complex molecular and cellular mechanisms, GLP-1 plays a vital role in the physiological and pathological processes of metabolic diseases like T2DM.232,233,241,259 (Fig. 2).Fig. 2 Mechanisms of Blood Glucose Reduction by GLP-1 in Pancreatic α, β, and δ Cells. This illustration demonstrates how GLP-1 reduces blood glucose levels by acting on different pancreatic cell types. In β cells, GLP-1(9–36) activates the GLP-1R, which increases cAMP levels, subsequently activating PKA and CREB, leading to the promotion of insulin secretion. The PI3K/Akt pathway enhances glucose sensitivity in β cells, promoting insulin secretion. This pathway also supports β cell survival and proliferation, ensuring an adequate β cell mass to maintain normal insulin secretion. This signaling cascade results in increased insulin gene expression, enhanced protein synthesis, improved cell survival, and reduced apoptosis. Additional metabolic effects include fatty acid oxidation, gluconeogenesis, and energy expenditure. In α cells, GLP-1(7-36) mainly regulates function through indirect mechanisms. GLP-1R expression is lower in α cells compared to β and δ cells, resulting in relatively less direct action of GLP-1 on α cells. Through paracrine effects via β cells, GLP-1 enhances insulin secretion, which in turn inhibits glucagon secretion from α cells. Additionally, GLP-1 promotes somatostatin secretion from δ cells, which inhibits glucagon secretion from α cells. GLP-1(7-36) can suppress glucagon secretion in α cells by increasing cAMP levels, activating PKA and EPAC, leading to a decrease in intracellular calcium concentration and reduced glucagon release. GLP-1(9–36) inhibits glucagon secretion by activating inhibitory G proteins (Gi/o) and suppressing PKA activity through a GCGR-dependent mechanism. By promoting the undocking of secretory granules (SG), GLP-1(9–36) reduces the number of granules available for exocytosis, thereby decreasing the release of glucagon. δ cells primarily secrete somatostatin. GLP-1(7-36) regulates somatostatin secretion by modulating calcium channels and affecting membrane potential changes. The action of GLP-1(7-36) on δ cells may be more indirect, such as through the influence on hormones secreted by β and α cells (insulin and glucagon), which indirectly affects δ cell somatostatin secretion. Additionally, somatostatin can inhibit gastrointestinal activities, reducing the secretion of pancreatic enzymes and gastric acid, thereby indirectly lowering the demand for glucagon

Role of GLP-1 in obesity

GLP-1 reduces appetite and food intake through its actions in the CNS.212,260,261 By interacting with receptors in the hypothalamus, GLP-1 influences satiety and reduces the consumption of food in both animals and humans.262 It functions not only in peripheral tissues but also directly within the CNS, crossing the blood-brain barrier or being produced centrally to act on the brain.262,263 GLP-1 regulates energy balance and food intake by acting on specific brain regions, especially the hypothalamus, a key area responsible for hunger and fullness sensations.264–266 The hypothalamus contains various neurons that respond to different nutritional signals and hormones, like GLP-1, to regulate food intake.265,266 When GLP-1 binds to its receptors in the hypothalamus, it activates specific neurons, including those that promote satiety (POMC/CART neurons) and inhibits those that induce hunger (NPY/AgRP neurons), thereby enhancing the feeling of fullness and reducing food intake.233,267

GLP-1 can slow down gastric emptying through its effects on smooth muscles and the nervous system in the gastrointestinal tract.264,268 Released at the gut’s end, GLP-1 acts on its receptors in the gastrointestinal tract, leading to reduced gastric muscle contractions and extended food retention in the stomach.264,269 Furthermore, GLP-1 can slow down gastric emptying by activating the vagus nerve, a part of the autonomic nervous system crucial for regulating the activities of the gastrointestinal tract.268 When activated, the vagus nerve can reduce the contraction of the stomach, thereby slowing down food emptying.269 The prolonged retention of food in the stomach enhances the feeling of fullness, naturally reducing overall food intake.270,271 Additionally, slower gastric emptying helps stabilize postprandial blood glucose levels. Reducing food intake and extending satiety are significant for weight management and loss. By regulating gastric emptying, GLP-1 not only aids in short-term appetite control but may also contribute positively to long-term energy balance and weight management.176

GLP-1RAs and diseases

As a rising star in recent years, GLP-1RAs are not only effective in metabolic diseases but also play a role in non-metabolic disorders, affecting multiple systems including the musculoskeletal, nervous, cardiovascular, and digestive systems, and can even have implications in oncological diseases.

Musculoskeletal system

Disorders associated with the musculoskeletal system often cause painful swelling and permanent damage in the joints of the body, especially the hips, knees and thumbs. These diseases may affect more people in today’s aging society. Because of the close relationship between risk factors in human metabolism and the expression of GLP-1R in the musculoskeletal system, GLP-1RAs may have great potential in the treatment of many diseases of the musculoskeletal system.15,272

GLP-1RAs and joint disorders

GLP-1RAs in OA

GLP-1R expression was detected via immunohistochemistry in articular chondrocytes from both normal and osteoarthritic individuals.273 The primary outcome of GLP-1R expression involves suppressing the release of cytokines into the synovial fluid, leading to a reduction in inflammation.274,275 This, in turn, diminishes additional downstream effects, including oxidative stress, the secretion of pro-degradative substances, modifications to cell phenotype (hypertrophy, M1/M2 macrophage phenotype, fibrosis), and damage or deterioration of joint cells (apoptosis, senescence).15,276

The activation of GLP-1R is linked to decreased NF-κB pathway activity Treatment with GLP-1RAs can effectively mitigate chondrocyte apoptosis caused by endoplasmic reticulum stress and alleviate the associated inflammatory response.277–280 This effect is accomplished through the inhibition of JNK, NF-κB, and other relevant signaling pathways.273 Moreover, GLP-1RAs could decelerate the progression of OA and mitigate pathological damage in a rat OA model.273 In addition, in a rat model of inflammatory OA induced by monoiodoacetic acid (MIA), researchers have shown that the activation of GLP-1R triggers the PKA/CREB signaling pathway, leading to a reduction in cartilage inflammation.281

Inflammation in OA is closely related to the activation of macrophages.282,283 These cells accumulate in the synovial membrane and subchondral bone, releasing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which promote the degradation of joint cartilage and the inflammatory response.284–286 Macrophages express GLP-1Rs, which are involved in regulating their inflammatory responses. Binding of GLP-1 or GLP-1RAs to these receptors can activate the cAMP/PKA signaling pathway, affecting key transcription factors like NF-κB.287,288

This binding initiates typical GPCR signaling, leading to G protein activation and increased intracellular cAMP.289 The rise in cAMP activates PKA, a versatile protein kinase that phosphorylates various target proteins.290–292 In macrophages, PKA regulates gene expression by phosphorylating transcription factors like CREB.293 CREB activation can promote the expression of anti-inflammatory genes while inhibiting inflammatory genes.294,295 In inflammation regulation, NF-κB is a key transcription factor.296–298 Typically, NF-κB binds to its inhibitor IκB in the cytoplasm.297,299 When IκB is phosphorylated and degraded, NF-κB can move to the nucleus, activating multiple inflammation-related genes.300,301 This not only affects the intracellular signaling of macrophages but also their response to the external environment, including their effects on chondrocytes and other synovial cells.302–305

GLP-1R signaling, through PKA, inhibits this process, possibly by promoting IκB stability or inhibiting its phosphorylation, thus reducing NF-κB activation and nuclear translocation.8,281 Through these mechanisms, GLP-1R signaling influences the production of inflammatory factors in macrophages.306 For example, the reduction in TNF-α, IL-1β, and IL-6 helps regulate local and systemic inflammatory responses.307,308 Additionally, GLP-1R signaling may affect other macrophage functions, such as phagocytosis, migration, and cell survival.281

By reducing macrophage-mediated inflammatory responses, GLP-1RAs have the potential to alleviate symptoms of OA, including pain and joint stiffness.281,309 Moreover, reducing inflammation may slow down the degradation of joint cartilage, providing long-term joint protection.310,311 GLP-1RAs also enhance autophagy, a process of cellular clearance of damaged and outdated components.13,312 Regulation of autophagy may help remove harmful proteins and other cellular debris accumulated under inflammatory conditions, which is potentially important for maintaining the health of joint tissues.313,314

In one study, OA was induced in rats by injecting MIA into the knee joint, mimicking the pathological changes of human OA.315 Subsequently, rats were treated with liraglutide through subcutaneous injection to observe its therapeutic effect on OA.315 The expression levels of GLP-1R, PKA/CREB signaling pathway components, and inflammation-related proteins (such as TNF-α, IL-1β, and IL-6) in the rat knee cartilage tissue were measured using Western blot and immunoprecipitation techniques.315 The results showed that, in the OA rat model, liraglutide could activate the PKA/CREB signaling pathway and inhibit the inflammatory response through this pathway, thereby alleviating OA symptoms.316 These findings provide scientific evidence for developing new OA treatment strategies, confirming the potential of GLP-1 agonists in treating OA.315–317

GLP-1R is expressed in human monocyte-derived macrophages and the mouse macrophage cell line RAW264.7.279,318 c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) involved in regulating cellular stress responses and inflammation.318 Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor involved in cell growth, differentiation, and inflammatory responses.319–321 Researchers found that activation of GLP-1R could play a key role in regulating macrophage polarization by adjusting the phosphorylation levels of JNK and STAT3.318,322 Macrophages have two polarization states, M1 typically has pro-inflammatory properties, while M2 has anti-inflammatory properties.323–325 Specifically, activation of GLP-1R leads to an increase in cAMP levels, which in turn activates PKA, a widely regulating enzyme of cellular functions, capable of phosphorylating a variety of target proteins, thereby initiating the PKA/CREB signaling pathway.326,327 This not only prevents the phosphorylation of JNK but also promotes the phosphorylation of STAT3, aiding the shift of macrophages to an anti-inflammatory M2 phenotype.327 In the inflammatory environment, the M1 to M2 shift promoted by GLP-1 is crucial for reducing the expression of inflammatory factors such as IL-6, TNF-α, and iNOS.8,15,328

Chondrocytes are the only cell type in joint cartilage, responsible for synthesizing and maintaining the integrity of the cartilage matrix.329,330 In degenerative joint diseases like OA, the metabolic balance of chondrocytes is disrupted, leading to the overproduction of degrading enzymes and inflammatory mediators, including iNOS, MMP-13, and ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5), which participate in cartilage degradation and inflammatory processes.331 iNOS (inducible nitric oxide synthase) produces nitric oxide (NO) during inflammation, modulating signal transduction; MMP-13 (matrix metalloproteinase-13) is involved in cartilage degradation;331 ADAMTS5 is closely related to cartilage damage and inflammation.332–334 The NO produced by iNOS, as a free radical, can regulate intracellular signal transduction and modulate the inflammatory response.335,336 The expression of iNOS is primarily activated by the NF-κB pathway, which is activated and translocated to the nucleus upon inflammatory stimulation (such as bacterial endotoxins or pro-inflammatory cytokines), thus increasing the transcription and expression of iNOS.337–339 GLP-1 can exert its anti-inflammatory effects by activating its receptor, GLP-1R.339 When GLP-1 binds to GLP-1R, it activates the cAMP signaling pathway, leading to increased cAMP levels.1,340 The rise in cAMP further activates PKA, which can inhibit the NF-κB signaling pathway, reducing the production of inflammatory factors such as iNOS and other inflammation-related proteins.12,340,341 The expression of MMP-13 is regulated by IL-1β and TNF-α. These factors promote the transcription of the MMP-13 gene by activating the MAPK and NF-κB signaling pathways.342–344 The GLP-1R signaling pathway may also affect the expression of MMP-13 and ADAMTS5, by reducing the signal transduction caused by IL-1β, thus decreasing their synthesis.345,346 GLP-1 may also reduce the expression of cartilage-degrading enzymes by inhibiting the MAPK pathway or activating anti-inflammatory pathways such as PI3K/Akt, thereby alleviating cartilage damage.206,347

In another study, treatment of primary mouse chondrocytes with liraglutide reduced the mRNA expression levels of iNOS, MMP-13, and ADAMTS5, leading to a decrease in the secretion of inflammatory markers, including NO, prostaglandin E, and IL-6.348 Similarly, in human chondrocytes stimulated by TNF, GLP-1 analogs (such as liraglutide) showed an anti-catabolic effect, reducing the mRNA expression of MMP-3, MMP-13, and ADAMTS5.349,350 At the same time, the levels of two important components of the cartilage matrix, proteoglycans (a large molecule and a major component of the cartilage matrix) and type II collagen (the main structural protein of cartilage), increased.349,350 This change suggests that liraglutide not only inhibits inflammation and cartilage degradation but may also promote the synthesis and accumulation of cartilage matrix, thereby helping to protect and repair joint cartilage.273 Furthermore, a study using the anterior cruciate ligament transection (ACLT) rat model further confirmed that subcutaneous injection of liraglutide at 50 μg/kg/day, whether for 3 weeks or 6 weeks, could reduce OARSI scores, highlighting the potential of liraglutide in treating joint degeneration.273

GLP-1RAs and RA

The role of GLP-1RA was also investigated in RA, which is characterized by chronic inflammation of the synovium and joint destruction. In fibroblast-like RA synoviocytes, the administration of lixisenatide resulted in a reduction in the inflammatory response.347 This was achieved by decreasing the expression of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8).15,351,352 Moreover, lixisenatide has been shown to inhibit matrix metalloproteinase (MMP) activity and effectively block various cell signaling pathways, including the JNK, activator protein-1, and NF-κB pathways.353 These findings confirm that in the synovium, GLP-1R is expressed on two different cell types, macrophages and fibroblast-like synoviocytes, which are specialized cells distributed within the synovial intima and subintima, and these cell types play important roles in hyaluronic acid synthesis, metabolite processing, and clearance of matrix degradation fragments.354

GLP-1RAs and musculoskeletal health

GLP-1RAs and bone

The quality of bone depends on bone metabolism, and the main factors affecting bone metabolism include osteoclasts, osteoblasts, and calcitonin.355–357 According to most related studies, osteoclasts and osteoblasts are indispensable for bone remodeling, and bone resorption and bone formation are mediated by osteoclasts and osteoblasts, respectively.358 GLP-1R is present in bone marrow stem cells (BMSCs),15,359 osteoblasts,15 osteocytes,360 and osteoclasts,361 and GLP-1RAs have the potential to impact these cells.

GLP-1RAs and osteoclasts The greater degree of bone degradation observed in mice lacking GLP-1R indicates that GLP-1R signaling suppresses osteoclast differentiation and bone resorption.362 In an experimental study in which osteoclast formation and bone resorption were induced in mice through lipopolysaccharide (LPS) administration, researchers discovered that simultaneous treatment with exendin-4 resulted in a significant decrease in the number of osteoclasts, the proportion of bone resorption pits, and the levels of the bone resorption marker CTX compared to injection with LPS alone.363 According to previous reports, exendin-4, a GLP-1RA, has the potential to inhibit LPS-induced osteoclast formation and bone resorption in vivo.363,364 This inhibition is believed to occur through the suppression of LPS-induced TNF-α production in macrophages.15 Studies have indicated that GLP-1R KO mice exhibit greater numbers of osteoclasts and greater bone resorption than wild-type controls.364 Additionally, µCT analysis revealed that, compared with their wild-type counterparts, hyperlipidemic rats treated with subcutaneous GLP-1 for 3 days exhibited increased bone mass in the femur and vertebrae.365

Diabetic patients have a higher risk of fractures than does the general population.366 Mice with type 1 diabetes (T1D) exhibit a reduction in bone mineral density (BMD) and compromised microstructural integrity.367 The administration of liraglutide also impeded osteoclastic bone formation, thereby inhibiting bone resorption and exerting protective effects on bone health in T1D mice.367 Specifically, liraglutide, both alone and in combination with insulin, effectively suppressed the formation of osteoclasts. This effect is achieved by reducing the expression of Trem2 and NFATc1 and downregulating the expression of CTSK and TRAP to inhibit bone resorption activity. These findings provide further evidence for the impact of GLP-1RAs on osteoclastic bone resorption.367 A study involving 12-week-old ovariectomized mice revealed that administering liraglutide for 4 weeks effectively prevented the loss of trabecular bone. The analysis of bone tissue morphology revealed that there were no alterations in the rate of bone formation or in the levels of calcitonin or sclerostin in these mice. These findings suggest that liraglutide specifically reduces bone resorption without influencing bone formation.368

Since GLP-1R is expressed in thyroid C cells and GLP-1 directly stimulates the secretion of calcitonin, which is a potent inhibitor of bone resorption in osteoclasts, GLP-1 may contribute to the nutrient-mediated reduction in bone resorption.369,370 Genetic disruption of GLP-1R signaling leads to cortical osteopenia and heightened bone fragility, primarily caused by increased bone resorption by osteoclasts. This change was accompanied by a decrease in thyroid calcitonin expression. Furthermore, the administration of exogenous GLP-1 resulted in elevated calcitonin expression in the thyroids of normal (wild-type) mice.362 The administration of calcitonin successfully reduced the levels of urinary deoxypyridinoline in GLP-1R knockout mice. Additionally, treatment with GLP-1RA and exendin-4 increased the expression of the calcitonin gene in the thyroids of normal (wild-type) mice. These findings provide evidence that the regulatory influence of endogenous GLP-1R signaling on bone resorption is likely mediated through pathways that involve calcitonin.362 Considering the expression of the GLP-1R in thyroid C cells and the ability of GLP-1 to stimulate calcitonin secretion through a cAMP-mediated mechanism in vitro, it is plausible that calcitonin plays a role in the alterations in bone metabolism observed in GLP-1R-treated animals.369,370 Later, quantitative real-time PCR analysis demonstrated that the administration of exendin-4, a GLP-1RA, resulted in significant upregulation of thyroid calcitonin mRNA levels in wild-type mice.362

GLP-1RAs and Osteoblasts Osteoblasts arise through the differentiation of mesenchymal stem cells and play a crucial role in the process of bone formation. Stimulating GLP-1R in BMSCs triggers the buildup of nuclear β-catenin, which, in turn, activates osteogenic genes by binding with TCF7L12.371 In osteoblasts, the administration of GLP-1 and GIP incretins suppressed the excessive expression of the pro-degradative enzymes MMP-3 and MMP-13 induced by IL-1β stimulation.372 In vitro, GLP-1 disrupts the ability of osteoblasts to survive and differentiate by triggering the activation of c-Fos, which is a proto-oncogene.373 In fact, when BMSCs are exposed to exendin-4, the expression of genes related to bone development factors such as Runx and Osterix, as well as genes responsible for producing the bone matrix such as Balp and Bglap, is upregulated. Moreover, stimulation of GLP-1R in BMSCs results in the accumulation of β-catenin in the cell nucleus. This accumulation facilitates the binding of β-catenin to TCF7L12, triggering the activation of genes associated with osteogenesis.371

In a study examining the effects of GLP-1RA on osteoporosis induced by ovariectomy in aged rats, administering exendin-4 for 16 weeks prevented deterioration of the trabecular microarchitecture and increased bone strength. This was achieved by inhibiting bone resorption through an increase in the OPG/RANKL ratio and promoting bone formation by enhancing the expression of osteoblast-specific transcription factors.374 Exendin-4 has also been shown to stimulate osteoblast activity and mitigate bone loss in an ovariectomized mouse model.374 Liraglutide can directly enhance bone formation in the MC3T3-E1 osteoblastic cell line. This effect is achieved through the activation of signaling pathways such as the ERK1/2, PI3K/AKT, and cAMP/PKA/β-cat-Ser675 pathways, which are mediated by GLP-1RAs.375 (Fig. 3).Fig. 3 The Effects of GLP-1RAs on osteoclasts and osteoblasts. GLP-1RAs aid in weight loss by regulating the gut-brain axis and interacting with leptin, while weight loss can alleviate the harmful effects of obesity on the body, particularly in knee OA, by reducing joint loading and inflammation. Obesity disrupts bone metabolism and leads to increased bone resorption, but GLP-1RAs can inhibit this damage and improve bone health by increasing the OPG/RANKL ratio, reducing osteoclast activity, and promoting bone formation

GLP-1RAs and muscle

GLP-1RAs and Muscle Atrophy In previous experiments, exendin-4 (Ex-4) inhibited the expression of myostatin (MSTN), atrophy-factor F-box only protein 32 (atrogin-1) and muscle ring finger protein 1 (MuRF-1) in dexamethasone-treated C2C12 myotubes.376–378 In a dexamethasone-induced muscle atrophy model, Ex-4 ameliorated muscle atrophy by inhibiting muscle atrophy factor and enhancing myogenic factors (MyoG and MyoD), thereby increasing muscle mass and function. In the muscle atrophy mouse model, Ex-4 also increased muscle mass and muscle fiber size and improved muscle function. In addition, treatment with the long-acting GLP-1RA duraglutide restored muscle mass and function in DBA/2J-mdx mice.379

GLP-1RAs, particularly PF1801, have demonstrated effective relief in inflammatory myopathies, such as polymyositis (PM), through preclinical studies.376,380 The therapeutic effects of PF1801 are primarily achieved by modulating several key proteins that play central roles in inflammation and cellular metabolism.380 Firstly, the expression of GLP-1R is enhanced in the inflamed muscle fibers under pathological conditions, revealing the critical role of GLP-1R in regulating the muscle’s response to inflammation.381 PF1801 activates these receptors, initiating a series of biological responses that influence the inflammatory state of muscle cells, thereby alleviating inflammation. Next, PF1801 exerts its effects by activating AMP-activated protein kinase (AMPK).382 As a central node in energy sensing and metabolic regulation, the activation of AMPK helps maintain cellular energy balance and prevents cell death due to energy depletion.383,384 Importantly, the activation of AMPK reduces the expression of phosphoglycerate mutase 5 (PGAM5), which plays a promotive role in cell necrosis by contributing to mitochondrial dysfunction and the production of reactive oxygen species (ROS).385–387 Thus, by inhibiting PGAM5, AMPK suppresses necrosis, reduces ROS accumulation, and mitigates oxidative stress.385,387 PF1801 displays its anti-inflammatory effects by lowering levels of inflammatory mediators such as TNFα, IL-6, and HMGB1, and enhances the cell’s antioxidant capability by upregulating molecules like Nfe2l2, Hmox1, Gclm, and Nqo1, which further improves cellular defense against oxidative stress and protects them from further damage.382 Through this sophisticated molecular regulation, PF1801 not only alleviates inflammation and necrosis in muscle fibers but also enhances the energy and antioxidant status of muscle cells.382 This contributes to maintaining muscle strength and reducing inflammation. This comprehensive change reflects how alterations in the expression of individual key proteins can impact the entire metabolic and inflammatory pathways, thereby improving disease conditions and enhancing therapeutic efficacy.376

GLP-1RAs in Enhancing Exercise Endurance Studies indicate that acute exercise and short-term endurance training significantly increase GLP-1 secretion in mice. In endurance-trained men, GLP-1 plasma concentrations are elevated immediately at 30 and 45 minutes after exercise.388 To confirm the role of GLP-1 in enhancing physical endurance and the possible mechanisms involved, an in vivo AAV-mediated GLP-1 overexpression model and an in vitro siRNA-mediated AMPK knockdown model were generated. We demonstrated that GLP-1 enhances physical endurance by inducing skeletal muscle remodeling, which may be mediated by GLP-1R/AMPK signaling.389 Overall, GLP-1 secretion is induced by exercise. Overexpression of GLP-1 in skeletal muscle can improve endurance. These results suggest that GLP-1 may improve exercise endurance in mice by enhancing skeletal muscle glycogen synthesis and glucose uptake. Mitochondrial content and function in skeletal muscle are regulated by GLP-1.389 The interaction between GLP-1 and its receptor GLP-1R initiates the AMPK signaling cascade within skeletal muscle tissue. This initiation precipitates a multitude of alterations in the cellular milieu, notably the augmentation of mitochondrial biogenesis-a mechanism responsible for the genesis of new mitochondria. Furthermore, GLP-1 augments mitochondrial efficacy, as manifested by the ameliorated oxidative metabolism of muscle tissue. This enhancement is demonstrable through an increase in mitochondrial DNA content, the upregulation of genes integral to mitochondrial biogenesis, and the increased expression of proteins pivotal in oxidative phosphorylation. These cellular transformations contribute significantly to enhanced endurance during exercise, thereby underscoring the critical role that GLP-1 plays in the regulation of mitochondrial function and content in skeletal muscle.389

GLP-1RAs and fat metabolism

GLP-1RAs work via numerous mechanisms that contribute to weight loss, one of the most well-known of which is the gut-brain axis.212,213,390 Within this axis, GLP-1 functions by acting on both the gut and the brain.391 Furthermore, the combination of GLP-1-mediated signaling and the adipocyte hormone leptin has recently garnered increased interest. Notably, leptin may serve as a crucial biological signal for GLP-1, working in synergy, to decrease food intake and body weight. The effects of the leptin-GLP-1 interaction may be governed by intracellular signaling pathways, including those involving phosphorylated STAT3 and PTP1B.15,392

In Wistar rats, a diet high in fat was found to lead to a decrease in the ratio of OPG/RANKL, which resulted in increased bone resorption and ultimately a reduction in bone mass. The administration of GLP-1RA or exendin-4 to rats fed a high-fat diet resulted in an increase in the OPG/RANKL ratio and a reduction in the degree of bone loss. It was observed that the treatment of rats on a high-fat diet with exendin-4 resulted in a decrease in the number of osteoclasts and the area of eroded surfaces, while there was an increase in the osteoid area, bone mass, and trabecular bone volume. These effects were compared to those of untreated controls that were also maintained on a high-fat diet.393 As a result, GLP-1RAs could mitigate the detrimental effects of hyperlipidemia-induced skeletal defects, leading to an improved prognosis in individuals with OA.

On the surface of the cartilage, there is a layer of special phospholipids. When a joint bears weight, it functions as a lubricant, playing a crucial role in enabling the joint to continue operating efficiently and smoothly. Altering the composition of this phospholipid layer can impact the functioning of the corresponding joint. For instance, changes in the composition of this phospholipid layer have been observed by researchers, along with their detrimental effects on the bones and joints of individuals with OA.394 Surprisingly, GLP-1RAs can influence the phospholipid structure and cytokines surrounding joints, leading to beneficial transformations that safeguard joints and even facilitate partial repair of any existing damage.395 (Fig. 4).Fig. 4 The Effects of GLP-1RAs on Musculoskeletal System. GLP-1RAs inhibit chondrocyte apoptosis, reduce inflammation, and protect articular chondrocytes in OA and RA through various mechanisms, including suppressing cytokine release, inhibiting the NF-κB pathway, and reducing inflammation-related gene expression. They have shown to reduce the inflammatory response by decreasing the expression of proinflammatory cytokines and inhibiting matrix metalloproteinase activity and cell signaling pathways. GLP-1R expression is found in macrophages and fibroblast-like synoviocytes, which are important for maintaining synovial fluid homeostasis. GLP-1R signaling stimulates calcitonin secretion, which inhibits bone resorption, and disruption of GLP-1R leads to increased bone resorption and decreased calcitonin expression. GLP-1RAs have pleiotropic effects on skeletal muscle, including inhibiting muscle atrophy, preserving muscle strength, and enhancing exercise endurance, through GLP-1R-mediated signaling pathways. GLP-1RAs can influence the composition of the phospholipid layer on cartilage, leading to beneficial effects on joint health and potentially facilitating repair of existing damage in individuals with OA

GLP-1RAs in nervous system

In the nervous system, GLP-1 can decrease oxidative stress and inflammatory responses, potentially through reducing the generation of ROS and decreasing the expression of inflammatory cytokines. Activation of its receptor by GLP-1 can promote the phosphorylation of CREB, subsequently fostering the expression of genes related to neuronal survival and regeneration.396–399

GLP-1RAs and nerve cells

GLP-1 can modulate peripheral nerves through the ERK (extracellular signal-regulated kinase) signaling pathway, reducing the occurrence of neurological dysfunction.400 Researchers have discovered that GLP-1RAs exhibit a noticeable increase in the level of phosphorylated ERK1/2 within the sciatic nerve of diabetic rats. This observation led them to speculate that GLP-1 analogs might possess distinct neurotrophic properties and exert protective effects specifically on the nerve.71,395,401–403

Astrocytes, the most abundant cell type in adult brain nerve tissue, have recently been recognized for their pivotal role in regulating glucose and energy homeostasis.404–406 These cells not only respond to signals from leptin and insulin but also adapt to alterations in brain metabolism to accommodate behavioral changes by controlling glucose transport.406,407 Furthermore, astrocytes express GLP-1R, which has been found to be crucial for their proper functioning.408 Studies have shown that the loss of GLP-1R in astrocytes can impair mitochondrial integrity, leading to the dysfunction and inhibition of glucose uptake and β-oxidation.407 GLP-1 inhibits glucose uptake in astrocytes and promotes beta-oxidation, which is essential for regulating energy balance in the brain and maintaining mitochondrial integrity.406 When GLP-1R is knocked out in astrocytes, it activates an integrated stress response, which affects the overall metabolic state by increasing the production of FGF21.405 This suggests that signaling through GLP-1R in astrocytes is crucial for maintaining the metabolic stability and functionality of the cells.406 FGF21 is recognized as a stress response factor that addresses mitochondrial dysfunction in cells. In astrocytes lacking GLP-1R, the increase in FGF21 is associated with improved systemic glucose homeostasis and memory formation.406 This indicates that FGF21 not only plays a role in cellular stress responses but also has a significant role in regulating brain function and systemic metabolism.406 Therefore, endogenous GLP-1R signaling in astrocytes plays a critical role in maintaining mitochondrial homeostasis and is dependent on FGF21 to effectively regulate glucose metabolism.406,407

GLP-1RAs can alleviate neuroinflammation by acting on the nervous system, thereby offering additional relief from pain in patients.6,409,410 During a previous experiment, researchers induced pain and observed symptoms of cognitive impairment in rats through spinal nerve ligation. Then, the researchers administered exendin-4 via intrathecal injection to the experimental rats and observed a reduction in pain sensitivity, alleviation of neural inflammation, and suppression of inflammatory factors such as IL-1β, TNF-α, and iNOS. This finding suggests a direct correlation between the analgesic effects of GLP-1R signaling and its Anti-neuroinflammatory activity.411 In another study, 3D fluorescence microscopy was used to eliminate proteins within chondrocytes in the subchondral bone of cartilage, resulting in bone transparency and the acquisition of high-resolution 3D images. By utilizing this methodology, researchers have revealed that GLP-1RAs can exhibit affect the axon terminals of sensory neurons. Ultimately, it was revealed that cholinergic fibers are present within the subchondral bone of individuals with OA, and the release of acetylcholine (Ach) triggered by vagus nerve stimulation plays a prominent role in combating inflammation across various diseases while also providing pain relief.412 Notably, GLP-1RAs, including exendin-4, have been shown to attenuate microglial activation, resulting in a reduction in the expression of proinflammatory cytokines such as TNF-α and IL-1β. By modulating inflammatory responses, GLP-1RAs can help prevent the degeneration of dopamine-producing cells.413 GLP-1RAs play a neuroprotective role in neurons by facilitating neuronal survival and promoting neuronal growth, thereby preserving the structural and functional integrity of synapses.6,14 Furthermore, GLP-1 signaling indirectly enhances and restores the insulin signaling pathway in neurons, leading to a reduction in the phosphorylation of insulin receptor substrates and the burden caused by monomeric α-synuclein.414 Together, these effects contribute to the protection of dopaminergic neurons (source). Exenatide has been shown to mitigate the phosphorylation of insulin receptor substrates and the accumulation of monomeric α-synuclein.414 By activating the GLP-1 signaling pathway, exenatide exhibits neuroprotective effects and safeguards dopaminergic neurons.5

The most well-known mechanism through which GLP-1RAs affect weight loss is through the endocrine pathway, but its role in the nervous system should not be overlooked.415–417 GLP-1RAs can exert their local effects by activating vagal dendritic terminals that innervate the gut.418–420 This activation holds the ability to modulate food consumption by reducing food intake and conveying signals of satiety to the brain.391 GLP-1 and GLP-1 analogs exert their effects on food intake and body weight through a myriad of neural substrates, encompassing several hypothalamic nuclei (including the arcuate nucleus of the hypothalamus, periventricular hypothalamus, and lateral hypothalamic area), hindbrain nuclei (such as the parabrachial nucleus and medial nucleus tractus solitarius), the ventral subregion of the hippocampus (vHP), and nuclei embedded within the mesolimbic reward circuitry (including the ventral tegmental area, VTA, and nucleus accumbens, NAc).421,422 Remarkably, GLP-1R activation in certain nuclei (such as the VTA, NAc, and vHP) elicits reductions in food intake and body weight without concurrent nausea responses.392

The relationship of inflammatory response and neurodegenerative disease

In the research conducted by Daniel J. Drucker’s team, the mechanism of anti-inflammatory action of GLP-1RAs was explored, revealing a key role for the CNS in regulating this anti-inflammatory effect.423 The study began by inducing inflammation in mice through the injection of various Toll-like receptor (TLR) agonists and then assessed the inflammation by measuring plasma tumor necrosis factor-alpha (TNF-α) levels.423 It was observed that the GLP-1RA, exendin-4, significantly reduced the TNF-α levels caused by various TLR agonists, indicating that exendin-4 can lower the TNF-α levels induced by multiple TLR agonists.423 The research further demonstrated that this anti-inflammatory effect was not mediated by GLP-1R in the blood or endothelial cells but required the GLP-1R in the CNS.

Additionally, to simulate sepsis caused by polymicrobial infection and assess the impact of GLP-1RAs, the study utilized a cecal content injection method. It was found that semaglutide, a long-acting GLP-1RA, could improve symptoms caused by sepsis, reduce body temperature, and decrease the bacterial load in multiple organs, along with the levels of inflammatory factors in plasma and lungs.423 These findings further confirmed the central role of the CNS in regulating the anti-inflammatory effects of GLP-1RAs, highlighting the potential application of GLP-1RAs in anti-inflammatory treatment.

The study also discovered the roles of α1-adrenergic and δ- and κ-opioid receptors in this process. Specifically, blocking the α1-adrenergic receptors with prazosin or the opioid receptors with nalbuphine interfered with the ability of GLP-1RAs to reduce plasma TNF-α levels, indicating the critical importance of these pathways in the anti-inflammatory effects mediated by GLP-1 activation. The α1-adrenergic receptors, found on the surface of cells, facilitate various physiological responses, including regulating vascular contraction and heart rate. The use of prazosin, an α1-adrenergic receptor blocker, showed that the ability of GLP-1RAs to reduce TNF-α in plasma was disrupted, signifying the vital role of α1-adrenergic receptors in the anti-inflammatory action of GLP-1RAs. Opioid receptors, which are associated with pain regulation, mood, and immune responses, include δ and κ types. The use of nalbuphine, a blocker of δ- and κ-opioid receptors, also disrupted the effect of GLP-1RAs on reducing TNF-α levels, highlighting the essential role of these opioid receptors in the anti-inflammatory effects mediated by GLP-1RAs.423

Furthermore, the study emphasized that neurons in specific brain regions, such as the hindbrain and hypothalamus, co-express GLP-1R along with α1-adrenergic and δ-opioid receptors, suggesting a localized mechanism within the CNS that could coordinate peripheral anti-inflammatory responses. This co-expression indicates a mechanism within the CNS allowing these neurons to sense and respond to the peripheral inflammatory state. Through the interaction of these receptors, the brain can receive signals of peripheral inflammation and respond through neural signaling, thereby modulating or alleviating the inflammatory response. This receptor co-expression on neurons in specific brain regions may enable the brain to finely regulate the body’s response to inflammation. For instance, when peripheral tissues become inflamed, the related signals might be transmitted to the brain through these receptors on the neurons, and the brain could then respond to these signals via neural pathways, thus regulating the level of peripheral inflammation.423

GLP-1RAs and AD

AD is a progressive and irreversible neurodegenerative disorder characterized by an unclear etiology and pathogenesis.424 In AD, GLP-1(7-36) amide inhibits IL-1β transcription and prevents cognitive dysfunction, amyloid precursor protein synthesis, and cell death. It also enhances learning and memory by promoting long-term potentiation (LTP).425,426 In a murine model of AD, the administration of GLP-1RAs effectively reduced the levels of pathological markers associated with AD. These markers include oligomeric antibodies and amyloid plaque load. Furthermore, GLP-1RAs have been shown to attenuate microglial activation and improve memory-related behaviors.71 Moreover, GLP-1RAs have demonstrated considerable therapeutic promise in animal models of both PD and AD.427–429 The compound NLY01 is particularly effective at attenuating the activity of proinflammatory microglia and preventing the transformation of astrocytes to a reactive phenotype. This activity is instrumental in safeguarding hippocampal neurons from the deleterious impacts of glutamate-induced excitotoxicity and hypoxic conditions. In the context of AD, where neuroinflammation and neurotoxicity are prominent pathological hallmarks, the modus operandi of NLY01 offers a potential therapeutic avenue to mitigate analogous pathological mechanisms inherent to this neurodegenerative condition.430

GLP-1RAs and PD

PD is a chronic neurodegenerative disorder that affects the CNS and is the second most prevalent neurodegenerative disease worldwide.14 GLP-1RAs are promising pharmacological agents for treating PD due to their potential to preserve the integrity and function of dopaminergic neurons. In addition to its effects on metabolic regulation, GLP-1, when synthesized within the brain, exhibits neuroprotective properties.397,427,431 A clinical trial titled “Liraglutide in Early Parkinson’s Disease” was published in the New England Journal of Medicine, exploring the effects of liraglutide on patients with early-stage PD diagnosed within the last three years.432 The research was a 14-month Phase II double-blind randomized controlled trial. The results showed that liraglutide had a modest positive effect on improving motor function and performed well in terms of safety and tolerability, although there were some manageable gastrointestinal side effects.432 The study emphasizes the need for further research into the potential benefits and risks of liraglutide in patients at different stages of PD.432

GLP-1RAs and addictive disorders

Researchers have discovered that semaglutide has the ability to reduce both recurrent alcohol consumption and overall alcohol intake in rats by more than 50%.433 Specifically, alcohol-dependent rats were administered semaglutide, which resulted in a significant reduction in their alcohol consumption.433 Further investigation into the mechanism underlying the alcohol-reducing effects of semaglutide suggested that this effect may involve the modulation of alcohol-induced rewards and punishments within the brain. Researchers have also shown that semaglutide impacts the reward and punishment systems in the brains of mice, particularly in the nucleus accumbens region, which is part of the limbic system.433 It is believed that alcohol activates the brain’s reward and punishment system, triggering the release of dopamine, a neurotransmitter associated with pleasure and reward, both in humans and animals. However, the administration of semaglutide appeared to block this process, potentially leading to a diminished alcohol-induced reward and punishment response within the body.433 Remarkably, compared with untreated rats, treated rats exhibited a significant reduction in alcohol intake, which was reduced by half.433 These findings highlight the potential therapeutic efficacy of semaglutide in mitigating alcohol consumption.434

Interestingly, a clinical study published in “Nature Metabolism” in 2023 investigated the restorative effects of liraglutide on impaired associative learning in individuals with obesity. The study utilized a single-blind, randomized, placebo-controlled, crossover design, combined with functional magnetic resonance imaging (fMRI), to analyze the performance of 54 participants (30 with normal insulin sensitivity and 24 with impaired insulin sensitivity) on sensory associative learning tasks while receiving liraglutide and placebo treatments.435 Liraglutide significantly enhanced associative learning abilities in obese individuals with impaired insulin sensitivity. It modulated neural activity in the ventral striatum and midbrain pathways, affecting brain areas related to metabolic signaling.435,436 Liraglutide improved task performance at the behavioral level and enhanced the encoding of adaptive prediction errors, which are crucial neural signals in the learning process.435 (Fig. 5).Fig. 5 The effects of GLP-1RAs on nervous system. GLP-1RAs have diverse effects, including alleviating neuroinflammation and pain in OA, reducing food intake and improving body weight, protecting peripheral nerves, maintaining astrocyte function and metabolic homeostasis, and showing potential therapeutic benefits in AD and PD. Semaglutide, a diabetes drug, can also reduce alcohol consumption by modulating the brain’s reward and punishment systems

GLP-1RAs in the cardiovascular system

In the cardiovascular system, GLP-1 can reduce cardiac ischemia-reperfusion injury through the activation of specific signaling pathways, such as the PI3K/Akt pathway.437,438 This involves modulating the cell apoptosis process, for example, by decreasing the Bax/Bcl-2 ratio in cardiomyocytes, reducing cytochrome C release, and caspase activation.438,439 GLP-1 can also enhance endothelial function by promoting the production of NO, possibly through activating eNOS, thereby affecting vasodilation, anti-inflammatory actions, and anti-atherosclerosis.43,192,440,441

GLP-1RAs and AS

AS is characterized by the formation of fibrofatty plaques within arterial walls and is one of the foremost global causes of mortality.5 GLP-1RAs, as exemplified by liraglutide and semaglutide, exhibit pronounced cardiovascular protective effects.43 Liraglutide and semaglutide have been demonstrated to be effective at reducing lipid and blood pressure levels through numerous scientific investigations, thereby contributing to the mitigation of AS and cardiovascular ailments.442 Preclinical studies have documented the inhibitory effects of GLP-1RAs on the development of AS in animal models.443 These agents exert their anti-atherosclerotic effects through various mechanisms, including by improving blood lipid profiles,444 preserving endothelial integrity and regulating endothelial function,445 as well as modulating inflammatory processes.70

GLP-1RAs confer substantial benefits for individuals with AS owing to their multifaceted impact on various aspects of cardiovascular health.39,40,446 Notably, GLP-1RAs exhibit pronounced efficacy in optimizing blood lipid profiles by effectively suppressing chylomicron secretion in the intestine, thereby mitigating the occurrence of postprandial hyperlipidemia.447 Moreover, these agents promote hemodynamic equilibrium,18 diminish thrombotic propensity,448 alleviate endothelial oxidative stress,449 attenuate inflammatory processes,450 and foster a favorable balance of the gut microbiota,451 all of which collectively contribute to the salutary effects of these agents in patients with AS.

GLP-1RAs have been shown to exert beneficial effects on the maintenance of endothelial integrity. One study suggested that GLP-1RAs exert direct endothelial protective effects by activating the GLP-1R-dependent AMPK/Akt/eNOS pathway. This pathway facilitates the generation of NO, thereby contributing to the preservation of vascular health and endothelial function. Additionally, GLP-1RAs facilitate the maintenance of endothelial barrier integrity, thus playing a crucial role in preventing vascular leakage.452 Endothelial cells exhibit enhanced NO production and concurrent suppression of endothelin formation, resulting in vascular smooth muscle relaxation and vasodilation mediated by the endothelium (e.g., GLP-1, exenatide, and liraglutide).453 Indeed, GLP-1RAs, including exenatide, liraglutide, and semaglutide, have been linked to the diminished expression of matrix metalloproteinases (MMPs).454–456 MMPs are a class of enzymes that play a crucial role in the breakdown of extracellular matrix components. Excessive MMP activity can lead to the weakening of fibrous caps and increase the risk of plaque rupture in atherosclerotic lesions.454 By reducing MMP expression, GLP-1R stimulation may help preserve the integrity of fibrous caps and mitigate the risk of plaque rupture.

GLP-1RAs have been shown to reduce the levels of systemic inflammatory markers.457,458 Importantly, the effective management of inflammation is widely acknowledged to play a crucial role in the prevention of cardiovascular diseases.459,460 The anti-inflammatory effects of GLP-1RAs contribute to the attenuation of atherosclerotic plaque lesion development through various mechanisms. First, GLP-1RAs have been shown to inhibit the expression and release of proinflammatory cytokines, such as IL-6 and TNF-α, thereby inhibiting the overall inflammatory response.461 GLP-1RAs can suppress the activation of nuclear factor-kappa B (NF-κB), a key transcription factor involved in the regulation of inflammatory processes.462 Inhibition of the NF-κB signaling pathway leads to the decreased production of inflammatory mediators, including adhesion molecules and chemokines, which are crucial for the recruitment of immune cells to sites of inflammation.463 In addition, liraglutide can delay the formation of AS by inducing cell cycle arrest in vascular smooth muscle cells through the AMPK pathway.5

GLP-1RAs and hypertension

The carotid body, a vital chemoreceptor in the human body, plays a pivotal role in the regulation of respiratory and cardiovascular activity, energy homeostasis, and blood glucose sensitivity.464 Notably, the carotid body expresses GLP-1R, which is implicated in the concurrent regulation of blood pressure and blood glucose.465 The downregulation of GLP-1R expression may represent a significant contributory factor to the co-occurrence of hypertension and hyperglycemia.466 One study proposed a novel mechanism wherein postprandial GLP-1 release, under normal physiological conditions, inhibits the activity of chemosensory cells in the carotid body, thereby counteracting sympathetic excitability mediated by elevated blood glucose or insulin levels.465 Impaired GLP-1 secretion or reduced GLP-1R expression may result in aberrantly heightened sympathetic excitation. However, the exogenous administration of GLP-1RAs can mitigate sympathetic excitability by suppressing the peripheral chemoreflex originating from the carotid body.467 Under hyperglycemic conditions, GLP-1RAs regulate hypertension by inhibiting carotid body function.468 Specifically, these agents can attenuate the excitability of carotid body cells and diminish sympathetic activation, ultimately leading to a reduction in sympathetic responses.465 This modulatory effect holds promise for ameliorating sympathetic activity in individuals with hypertension, as these agents lower blood pressure levels.469 Importantly, the “GLP-1-carotid body pathway” may represent a novel therapeutic target for managing cardiovascular metabolism and treating patients with diabetes and hypertension who exhibit heightened sympathetic activity.465 (Fig. 6).Fig. 6 The Effects of GLP-1RAs on Carotid Body Activation. GLP-1 by inhibiting the chemoreception in carotid body cell activity to adjust the new mechanism of sympathetic nerve excitability, and points out that GLP-1 agonists can inhibit the origin of the carotid body around chemical reflection to lighten the sympathetic nerve excitability, which is expected to improve the sympathetic activity of the patients with high blood pressure, reduce blood pressure levels

GLP-1RAs and heart failure

The prevalence of left ventricular ejection fraction (LVEF)-preserved heart failure continues to increase. The symptoms in patients are severe and often accompanied by functional impairments, especially in the obese population. Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases, with patients bearing a high symptomatic burden and physical limitations that impact their daily lives. These limitations include fatigue, shortness of breath, reduced exercise capacity, and limb swelling. Currently, there are no approved targeted therapies for LVEF-preserved heart failure associated with obesity. Moreover, GLP-1R has not yet been identified on human myocardial cells, negating any direct effects of GLP-1RAs on myocardial cells.470

Recently, studies have shown that the GLP-1RA Meg peptide also enters the ejection fraction reserve following heart failure therapy. The results of a trial of semaglutide in obese patients with HFpEF showed a significant amelioration of symptoms and improvements in motor function and weight loss compared with patients treated with a placebo.470 In this study, researchers randomized 529 patients with heart failure with a preserved ejection fraction and body mass index (weight in kilograms in the square of the height in meters) ≥30 to receive once-weekly injections of semaglutide (2.4 mg) or placebo for 52 weeks. The two primary endpoints were the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS, which ranges from 0 to 100) and the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). Higher scores indicate fewer symptoms and physical limitations and weight change from baseline. The confirmatory secondary endpoints included the change in the 6-min walking distance, a hierarchical composite of death and heart failure events; the difference between the change in the KCCQ-CSS and the change in the 6-min walking distance; and the change in the C-reactive protein (CRP) level.470 In this trial, semaglutide benefited patients with heart failure and preserved ejection fraction by intervening with upstream metabolic drivers. This agent differs from earlier therapies that were designed to reduce myocardial loading or induce neurohumoral blockade. These positive results indicate that the change in myocardial cells may not be the primary driver of HFpEF; instead, the multisystem pathologic processes that are associated with this condition have long been well established as drivers of its clinical presentation and outcomes.470

One could argue that the success of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and now of GLP-1RAs, suggests that metabolic abnormalities play an important role in driving HFpEF.470 SGLT2 inhibition is also known to benefit patients with heart failure and a reduced ejection fraction.471 The mechanisms by which SGLT2 inhibitors treat heart failure include lowering blood glucose levels by inhibiting the SGLT2 protein in the renal tubules and reducing glucose reabsorption in the tubules.472 Promoting the urinary excretion of sodium and water reduces fluid retention and hypervolaemia, thereby reducing the load on the heart.473 It also improves myocardial energy metabolism, increases fatty acid oxidation in the myocardium, and improves myocardial energy supply.474 Moreover, these agents reduce the risks of myocardial inflammation and fibrosis and improve cardiac structure and function.475 By the way, a clinical study published in “Nature Metabolism” detailed the effects of semaglutide and dapagliflozin (an SGLT2 inhibitor) on blood sugar control in patients with T2DM of different pathophysiological types.476 It was found that semaglutide performed better than dapagliflozin in reducing HbA1c levels.476 The study results suggest that semaglutide may be a more suitable choice for patients with severe insulin deficiency, while dapagliflozin might be effective for a broader range of patients with metabolic abnormalities.476

If SGLT2 inhibitors and GLP-1RAs are effective in patients with heart failure (regardless of whether the ejection fraction is reduced or preserved), the commonalities between the two types of heart failure may be greater than is often thought. If so, the two types of heart failure may be very similar, except that the cause of heart failure with a preserved ejection fraction may not be the same as that with a reduced ejection fraction.477–479 If this is indeed the case, then both types of heart failure are syndromes caused by multiple metabolic and inflammatory changes; however, heart failure with reduced ejection fraction also has a regional cause. Therefore, intrinsic cardiac load and capacity do not improve in patients with heart failure with reduced ejection fraction, and patients HFpEF benefit only from the treatment of abnormal metabolism and inflammation.475,480,481

The encouraging results obtained with semaglutide in patients with heart failure and a preserved ejection fraction may provide a new option for this patient population, in which additional therapy, as well as another upstream therapy for patients with a higher BMI who have indications for this condition, is urgently needed. The clinical translation of these trial results, which will be important for the comparison of GLP-1RAs with SGLT2 inhibitors in the treatment of patients with heart failure and a preserved ejection fraction, remains to be determined.470,478,482–484

GLP-1RAs in the digestive system

Treatment with GLP-1RAs can alleviate insulin signaling by reducing the phosphorylation of Akt protein (Decreased Akt-P) and activating Protein Kinase C-ε (PKC-ε).485,486 This affects the synthesis of triacylglycerol (TAG), phosphatidic acid (di-P PA), and diacylglycerol (DAG) in the liver.206,487 These changes lead to a reduction in the production of non-esterified fatty acids (LCFAs) and glucose, as well as a decrease in the synthesis of VLDL (Very Low-Density Lipoprotein).3

GLP-1RAs and NAFLD/NASH

When dietary nutrients are ingested, endogenous incretins (GIP and GLP-1) activate K and L cells in the gut, which then secrete GIP and GLP-1.488–490 In the pancreas, this stimulates the secretion of insulin and inhibits the secretion of glucagon.491 In the brain, it reduces appetite and improves satiety.130,133 In the gastrointestinal tract, it lowers the synthesis and secretion of triglycerides.491 By regulating appetite, insulin secretion, and lipid metabolism, GLP-1RAs have potential benefits in the treatment of NAFLD, NASH, and T2DM.130,492,493

NASH is a liver disease primarily caused by fat accumulation, which can progress to liver fibrosis, cirrhosis, or even liver cancer.494–498 The role of GLP-1 in NASH has garnered attention due to its potential in regulating metabolism, improving insulin sensitivity, and exerting anti-inflammatory effects.17,499–503 Insulin resistance, a common occurrence in NASH patients, is a key driver of the disease’s progression.504–506 GLP-1 enhances the insulin signaling pathway in the liver by activating the GLP-1R, especially through the phosphorylation of insulin receptor substrates and the activation of the PI3K/Akt signaling pathway, thereby increasing hepatic insulin sensitivity, facilitating glucose uptake and utilization, and reducing hepatic gluconeogenesis.3,507

GLP-1RAs reduce liver fat accumulation by activating AMPK, which inhibits fatty acid synthesis enzymes and promotes fatty acid β-oxidation, thus diminishing lipid droplet accumulation in hepatocytes.508–511 Additionally, GLP-1 mitigates liver inflammation and fibrosis by inhibiting the NF-κB pathway, reducing the release of pro-inflammatory cytokines such as TNF-α and IL-6, and thus suppressing inflammatory pathways.307,413

In terms of apoptosis inhibition, GLP-1 activates the PI3K/Akt signaling pathway, enhances the expression of the anti-apoptotic protein Bcl-2, and inhibits the activation of caspase family proteins, reducing cell apoptosis.206 This helps prevent the progression of NASH to liver fibrosis and cirrhosis. The weight-loss effect of GLP-1RAs also benefits NASH improvement, by reducing appetite and increasing energy expenditure to promote weight loss, thereby indirectly ameliorating NASH.206,512 Thus, GLP-1 and its agonists slow down the progression of NASH and may positively impact the reversal of liver fibrosis.513,514 These signaling pathways suggest that GLP-1 and its receptor agonists may influence the progression of NASH through multiple mechanisms, providing several potential therapeutic targets including: FOXO1, a transcription factor that plays a critical role in regulating glucose and lipid metabolism. GLP-1 can improve abnormalities in glucose metabolism and excessive lipid accumulation by modulating the activity of FOXO1.5,514 Sirt1, a protein deacetylase, plays a key role in delaying cellular aging and regulating metabolism.515–517 GLP-1 may improve the liver’s antioxidant capacity and metabolic function by activating Sirt1, thereby helping to alleviate the pathological changes associated with NASH.

A 2023 study published in the “Journal of Hepatology” reported on a Phase IIa trial aimed at evaluating the efficacy and safety of efinopegdutide in patients with NAFLD, comparing it to semaglutide.144 Efinopegdutide is a dual agonist for GLP-1R and GIPR.144 The study used a randomized, open-label design and employed magnetic resonance imaging technology (MRI-PDFF) to measure liver fat content (LFC) after 24 weeks of treatment. Results showed that efinopegdutide was more effective in reducing LFC compared to semaglutide. Additionally, the study assessed weight and metabolic responses, finding that efinopegdutide’s tolerability was similar to that of semaglutide, although certain gastrointestinal side effects were more common. Overall, efinopegdutide emerged as a promising option for the treatment of NAFLD.144

GLP-1RAs and gastrointestinal cancers

GLP-1 and its receptor agonists show some potential in the treatment of gastrointestinal cancers, although this remains an emerging area of research.518–521

Hepatocellular carcinoma (HCC)

Initially developed for treating diabetes, GLP-1RAs have shown potential in treating NASH, which is closely related to HCC.513 Studies suggest that the anti-inflammatory and metabolic effects of GLP-1RAs might also influence the progression of liver diseases, including HCC.503,512,518 These effects include modulating cell proliferation, inflammation, and oxidative stress in liver cells, all of which are key factors in the development and progression of HCC.513,522 In a mouse model induced with NASH-related HCC, treatment with liraglutide (a type of GLP-1RA) was shown to prevent the progression of hepatocellular carcinoma.518 This was observed through improved glycemic control, reduced occurrence of liver cancer, and better liver histology compared to the control group.518 Studies indicate that liraglutide may inhibit liver carcinogenesis through its metabolic effects, suggesting that GLP-1RAs could potentially play a role in preventing or managing HCC in the context of NASH.523 Not only hepatocellular carcinoma, but GLP-1 has also shown potential in the treatment of other gastrointestinal tumors.524,525

Pancreatic cancer

Researchers first compared the expression of GLP-1R in human pancreatic cancer tissues with adjacent non-tumorous pancreatic tissues, finding generally lower or absent expression of GLP-1R in pancreatic cancer tissues.520 Subsequently, the study observed that treatment with liraglutide, both in vitro (cell culture models) and in vivo (mouse models), inhibited the tumor formation and metastatic capabilities of pancreatic cancer cells by activating GLP-1R.520 The anti-tumor effect of liraglutide is related to its inhibition of the PI3K/Akt signaling pathway, as the activation of Akt is crucial for promoting cell survival and proliferation, and liraglutide can inhibit this process in a dose-dependent manner.520,526 In the context of T2DM, liraglutide, by regulating the PI3K/Akt pathway and activating GLP-1R, effectively inhibits the growth and spread of pancreatic cancer cells.520

Colorectal cancer

The potential impact of GLP-1RAs on colorectal cancer (CRC) treatment is achieved through the modulation of Bone Morphogenetic Protein 4 (BMP4).519 In T2DM and CRC, the regulation of BMP4 is abnormal, which is a key focus of the research.519 Specifically, high blood glucose-induced insulin resistance in CRC cells leads to increased BMP4 expression, which activates the BMP4-Smad1/5/8 signaling pathway.519 The activation of this pathway enhances cell proliferation and metastatic capabilities by promoting epithelial-mesenchymal transition (EMT), thereby increasing the invasiveness and metastatic potential of tumors. However, GLP-1RAs have been shown to reduce BMP4 levels through exogenous administration. Studies have shown that treating CRC cells with GLP-1RA can inhibit cell proliferation induced by insulin resistance by downregulating BMP4. Therefore, BMP4 becomes a potential therapeutic target in CRC, especially in a diabetic context where high blood glucose significantly affects cancer progression through the BMP4 pathway.519 Ultimately, GLP-1RA, by regulating BMP4 and its effects on cell proliferation and metastasis, provides a promising treatment approach.519 This not only demonstrates the role of GLP-1RA in diabetes management but also offers potential for integrating diabetes and cancer treatment.520 This finding emphasizes the importance of considering metabolic status in cancer treatment and the necessity for further research in this area.519 While early models have shown promising results, the application of GLP-1RAs in cancer treatment has not yet been established and requires further clinical trials.527

Conclusions and perspective

Primarily recognized for their role in diabetes mellitus treatment, GLP-1RAs have demonstrated significant benefits in cardiovascular health, skeletal muscle-related diseases, obesity management, and neurodegenerative conditions, among others. In this review, we delved into the multifaceted role of GLP-1R, especially its significance in disease contexts beyond traditional glucose metabolism. It explored the mechanisms of action of GLP-1RAs and their therapeutic potential in a wide array of diseases, such as diabetes mellitus, providing new insights into metabolic disease management. These findings underscore the multifunctionality of GLP-1R as a therapeutic target and its involvement in various biological processes, emphasizing its role in addressing complex disease mechanisms. GLP-1 acts on the GLP-1R, activating multiple intracellular signaling pathways, including the cAMP/PKA pathway, the PI3K/Akt signaling pathway, and pathways related to anti-inflammatory and anti-oxidative stress responses, among others. These pathways play a crucial role in its wide-ranging therapeutic effects, extending the benefits of GLP-1RAs beyond metabolic diseases. While the therapeutic benefits of GLP-1RAs in diabetes management are well-established, their emerging role in other diseases suggests novel treatment strategies. Conclusively, research on GLP-1R and its agonists marks a promising direction in metabolic disease therapy, extending their potential beyond glucose regulation and offering hope for more comprehensive approaches in addressing metabolic diseases. This research necessitates continued exploration, potentially revolutionizing future therapeutic strategies.

In the intensely competitive GLP-1 drug market, simply enhancing drug efficacy is no longer sufficient to make new products stand out. Looking ahead, the key strategies for product innovation and differentiation are likely to focus on five main directions: expanding the therapeutic indications, achieving precision treatment with multiple biological targets, optimizing the clinical application of drug combinations, developing new formulations of oral medications, and extending the duration of drug action. These strategies not only illustrate the depth and breadth of pharmaceutical research but also signify the frontier of future medical innovations. Firstly, expanding indications is a current hotspot in GLP-1 drug research. GLP-1 drugs have been found applicable for various diseases such as cardiovascular disease, NASH, AD, and chronic kidney disease. For instance, semaglutide has been approved and is being researched for indications including obesity, T2DM, reducing cardiovascular risk, chronic kidney disease, NAFLD, and AD, indicating that the development of new indications could provide new growth opportunities for GLP-1 drugs. Secondly, efficacy is the core criterion for evaluating drugs, and currently, multi-target GLP-1 drugs have shown better efficacy. For example, triple-target agonists like retatrutide are leading multi-target GLP-1 drugs. Moreover, combination therapies have demonstrated significant advantages, such as Novo Nordisk’s CagriSema (semaglutide + cagrilintide), which shows superior glycemic control and weight reduction effects compared to semaglutide alone, demonstrating that combination therapy can achieve more than the sum of its parts while reducing side effects.117 Additionally, to improve patient compliance, it is crucial to extend the drug’s half-life. This has been achieved through techniques such as peptide sequence modification, peptide lipidation, albumin fusion, and Fc fusion. For example, scientists are developing GLP-1 drugs that require only monthly injections. Lastly, considering some patients’ resistance to injections, oral medications have become the preferred option. However, the oral GLP-1 product, Rybelsus, has low bioavailability and requires cumbersome daily administration, which reduces its convenience. Therefore, enhancing bioavailability and stability will be key in the future, although breakthroughs in once-weekly oral GLP-1 drugs are still awaited. With the increasing prevalence of metabolic diseases globally, interventions targeting GLP-1R could play an important role in reducing the burden of these conditions. Collaborative efforts among researchers, clinicians, and pharmaceutical developers are essential to translate these scientific insights into effective and accessible treatments.

Acknowledgements

This study was performed with the support of the National Natural Science Foundation of China (82002339, 81820108020), Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System (BJ1-9000-22-4002). BioRender (https://www.biorender.com/) was used to create the Fig. 2.

Author contributions

Z.Z., Y.Z. and J.G. drafted and conceived the initial manuscript. J.G. and C.Z. provided the essential assistant for our final manuscript. Z.Z., Y.M., Y.T., Y.Z. and Y.P. drew the figures and arranged the tables. All authors have read and approved the article.

Competing interests

The authors declare no competing interests.

These authors contributed equally: Zhikai Zheng, Yao Zong
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References

1. Marzook A Tomas A Jones B The interplay of glucagon-like peptide-1 receptor trafficking and signalling in pancreatic beta cells Front Endocrinol. (Lausanne) 2021 12 678055 10.3389/fendo.2021.678055 34040588
Marzook, A., Tomas, A. & Jones, B. The interplay of glucagon-like peptide-1 receptor trafficking and signalling in pancreatic beta cells. Front Endocrinol. (Lausanne) 12, 678055 (2021).34040588
2. Ibrahim, S. S. et al. The effect of GLP-1R agonists on the medical triad of obesity, diabetes, and cancer. Cancer Metastasis Rev. 43, 141–156 (2024).
3. MacDonald PE The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion Diabetes 2002 51 S434 442 10.2337/diabetes.51.2007.S434 12475787
MacDonald, P. E. et al. The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion. Diabetes 51, S434–442 (2002).12475787
4. Bu T Glucagon-like peptide-1: New regulator in lipid metabolism Diab Metab. J. 2024 48 354 372 10.4093/dmj.2023.0277
Bu, T. et al. Glucagon-like peptide-1: New regulator in lipid metabolism. Diab Metab. J. 48, 354–372 (2024).
5. Zhao X GLP-1 receptor agonists: beyond their pancreatic effects Front Endocrinol. (Lausanne) 2021 12 721135 10.3389/fendo.2021.721135 34497589
Zhao, X. et al. GLP-1 receptor agonists: beyond their pancreatic effects. Front Endocrinol. (Lausanne) 12, 721135 (2021).34497589
6. Diz-Chaves, Y. et al. Anti-inflammatory effects of GLP-1 receptor activation in the brain in neurodegenerative diseases. Int. J. Mol. Sci. 23, 9583 (2022).
7. Toft-Nielsen MB Madsbad S Holst JJ Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes J. Clin. Endocrinol. Metab. 2001 86 3853 3860 10.1210/jcem.86.8.7743 11502823
Toft-Nielsen, M. B., Madsbad, S. & Holst, J. J. Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes. J. Clin. Endocrinol. Metab. 86, 3853–3860 (2001).11502823
8. Chen J GLP-1 receptor agonist as a modulator of innate immunity Front Immunol. 2022 13 997578 10.3389/fimmu.2022.997578 36569936
Chen, J. et al. GLP-1 receptor agonist as a modulator of innate immunity. Front Immunol. 13, 997578 (2022).36569936
9. Heinla K GLP-1 receptor agonists induce growth hormone secretion in healthy volunteers Diab Ther. 2023 14 777 786 10.1007/s13300-023-01381-w
Heinla, K. et al. GLP-1 receptor agonists induce growth hormone secretion in healthy volunteers. Diab Ther. 14, 777–786 (2023).
10. Andreasen CR Andersen A Knop FK Vilsbøll T How glucagon-like peptide 1 receptor agonists work Endocr. Connect 2021 10 R200 r212 10.1530/EC-21-0130 34137731
Andreasen, C. R., Andersen, A., Knop, F. K. & Vilsbøll, T. How glucagon-like peptide 1 receptor agonists work. Endocr. Connect 10, R200–r212 (2021).34137731
11. Mojsov S Weir GC Habener JF Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas J. Clin. Invest 1987 79 616 619 10.1172/JCI112855 3543057
Mojsov, S., Weir, G. C. & Habener, J. F. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Invest 79, 616–619 (1987).3543057
12. Guo W Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog Mol. Metab. 2023 75 101762 10.1016/j.molmet.2023.101762 37364710
Guo, W. et al. Discovery of ecnoglutide - A novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog. Mol. Metab. 75, 101762 (2023).37364710
13. Du H Meng X Yao Y Xu J The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease Front Endocrinol. (Lausanne) 2022 13 1033479 10.3389/fendo.2022.1033479 36465634
Du, H., Meng, X., Yao, Y. & Xu, J. The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease. Front Endocrinol. (Lausanne) 13, 1033479 (2022).36465634
14. Reich N Hölscher C The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review Front Neurosci. 2022 16 970925 10.3389/fnins.2022.970925 36117625
Reich, N. & Hölscher, C. The neuroprotective effects of glucagon-like peptide 1 in Alzheimer’s and Parkinson’s disease: An in-depth review. Front Neurosci. 16, 970925 (2022).36117625
15. Meurot C Targeting the GLP-1/GLP-1R axis to treat osteoarthritis: A new opportunity? J. Orthop. Transl. 2022 32 121 129
Meurot, C. et al. Targeting the GLP-1/GLP-1R axis to treat osteoarthritis: A new opportunity? J. Orthop. Transl. 32, 121–129 (2022).
16. de Lemos JA Tirzepatide reduces 24-hour ambulatory blood pressure in adults with body mass index ≥27 kg/m(2): SURMOUNT-1 ambulatory blood pressure monitoring substudy Hypertension 2024 81 e41 e43 10.1161/HYPERTENSIONAHA.123.22022 38314555
de Lemos, J. A. et al. Tirzepatide reduces 24-hour ambulatory blood pressure in adults with body mass index ≥27 kg/m(2): SURMOUNT-1 ambulatory blood pressure monitoring substudy. Hypertension 81, e41–e43 (2024).38314555
17. Li QX GLP-1 and underlying beneficial actions in Alzheimer’s disease, hypertension, and NASH Front Endocrinol. (Lausanne) 2021 12 721198 10.3389/fendo.2021.721198 34552561
Li, Q. X. et al. GLP-1 and underlying beneficial actions in Alzheimer’s disease, hypertension, and NASH. Front Endocrinol. (Lausanne) 12, 721198 (2021).34552561
18. Nielsen R Effect of liraglutide on myocardial glucose uptake and blood flow in stable chronic heart failure patients: A double-blind, randomized, placebo-controlled LIVE sub-study J. Nucl. Cardiol. 2019 26 585 597 10.1007/s12350-017-1000-2 28770459
Nielsen, R. et al. Effect of liraglutide on myocardial glucose uptake and blood flow in stable chronic heart failure patients: A double-blind, randomized, placebo-controlled LIVE sub-study. J. Nucl. Cardiol. 26, 585–597 (2019).28770459
19. Mundil D Cameron-Vendrig A Husain M GLP-1 receptor agonists: A clinical perspective on cardiovascular effects Diab Vasc. Dis. Res. 2012 9 95 108 10.1177/1479164112441526 22496442
Mundil, D., Cameron-Vendrig, A. & Husain, M. GLP-1 receptor agonists: A clinical perspective on cardiovascular effects. Diab Vasc. Dis. Res. 9, 95–108 (2012).22496442
20. Lund PK Goodman RH Dee PC Habener JF Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem Proc. Natl. Acad. Sci. USA 1982 79 345 349 10.1073/pnas.79.2.345 7043459
Lund, P. K., Goodman, R. H., Dee, P. C. & Habener, J. F. Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem. Proc. Natl. Acad. Sci. USA 79, 345–349 (1982).7043459
21. Bell GI Santerre RF Mullenbach GT Hamster preproglucagon contains the sequence of glucagon and two related peptides Nature 1983 302 716 718 10.1038/302716a0 6835407
Bell, G. I., Santerre, R. F. & Mullenbach, G. T. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 302, 716–718 (1983).6835407
22. Bell GI Sanchez-Pescador R Laybourn PJ Najarian RC Exon duplication and divergence in the human preproglucagon gene Nature 1983 304 368 371 10.1038/304368a0 6877358
Bell, G. I., Sanchez-Pescador, R., Laybourn, P. J. & Najarian, R. C. Exon duplication and divergence in the human preproglucagon gene. Nature 304, 368–371 (1983).6877358
23. Holst JJ Orskov C Nielsen OV Schwartz TW Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut FEBS Lett. 1987 211 169 174 10.1016/0014-5793(87)81430-8 3542566
Holst, J. J., Orskov, C., Nielsen, O. V. & Schwartz, T. W. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 211, 169–174 (1987).3542566
24. Kreymann B Williams G Ghatei MA Bloom SR Glucagon-like peptide-1 7-36: A physiological incretin in man Lancet 1987 2 1300 1304 10.1016/S0140-6736(87)91194-9 2890903
Kreymann, B., Williams, G., Ghatei, M. A. & Bloom, S. R. Glucagon-like peptide-1 7-36: A physiological incretin in man. Lancet 2, 1300–1304 (1987).2890903
25. Eng J Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas J. Biol. Chem. 1992 267 7402 7405 10.1016/S0021-9258(18)42531-8 1313797
Eng, J. et al. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J. Biol. Chem. 267, 7402–7405 (1992).1313797
26. Day JW A new glucagon and GLP-1 co-agonist eliminates obesity in rodents Nat. Chem. Biol. 2009 5 749 757 10.1038/nchembio.209 19597507
Day, J. W. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009).19597507
27. Finan B Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans Sci. Transl. Med. 2013 5 209ra151 10.1126/scitranslmed.3007218 24174327
Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5, 209ra151 (2013).24174327
28. Finan B A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents Nat. Med 2015 21 27 36 10.1038/nm.3761 25485909
Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med 21, 27–36 (2015).25485909
29. D’Alessio D Is GLP-1 a hormone: Whether and When? J. Diab Investig. 2016 7 50 55 10.1111/jdi.12466
D’Alessio, D. Is GLP-1 a hormone: Whether and When? J. Diab Investig. 7, 50–55 (2016).
30. Thorens B. Expression cloning of the pancreatic β cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proceedings of the National Academy of Sciences of the United States of America, 89, 8641–8645 (United States, 1992).
31. Deacon CF Holst JJ Immunoassays for the incretin hormones GIP and GLP-1 Best. Pr. Res Clin. Endocrinol. Metab. 2009 23 425 432 10.1016/j.beem.2009.03.006
Deacon, C. F. & Holst, J. J. Immunoassays for the incretin hormones GIP and GLP-1. Best. Pr. Res Clin. Endocrinol. Metab. 23, 425–432 (2009).
32. Malik J Roohi N GLP-1, a powerful physiological incretin: an update J. Biol. Regul. Homeost. Agents 2018 32 1171 1176 30334409
Malik, J. & Roohi, N. GLP-1, a powerful physiological incretin: an update. J. Biol. Regul. Homeost. Agents 32, 1171–1176 (2018).30334409
33. Nadkarni P Chepurny OG Holz GG Regulation of glucose homeostasis by GLP-1 Prog. Mol. Biol. Transl. Sci. 2014 121 23 65 10.1016/B978-0-12-800101-1.00002-8 24373234
Nadkarni, P., Chepurny, O. G. & Holz, G. G. Regulation of glucose homeostasis by GLP-1. Prog. Mol. Biol. Transl. Sci. 121, 23–65 (2014).24373234
34. Campbell JE Drucker DJ Pharmacology, physiology, and mechanisms of incretin hormone action Cell Metab. 2013 17 819 837 10.1016/j.cmet.2013.04.008 23684623
Campbell, J. E. & Drucker, D. J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17, 819–837 (2013).23684623
35. Deacon CF Circulation and degradation of GIP and GLP-1 Horm. Metab. Res 2004 36 761 765 10.1055/s-2004-826160 15655705
Deacon, C. F. Circulation and degradation of GIP and GLP-1. Horm. Metab. Res 36, 761–765 (2004).15655705
36. Mentlein R Mechanisms underlying the rapid degradation and elimination of the incretin hormones GLP-1 and GIP Best. Pr. Res Clin. Endocrinol. Metab. 2009 23 443 452 10.1016/j.beem.2009.03.005
Mentlein, R. Mechanisms underlying the rapid degradation and elimination of the incretin hormones GLP-1 and GIP. Best. Pr. Res Clin. Endocrinol. Metab. 23, 443–452 (2009).
37. Drucker DJ The biology of incretin hormones Cell Metab. 2006 3 153 165 10.1016/j.cmet.2006.01.004 16517403
Drucker, D. J. The biology of incretin hormones. Cell Metab. 3, 153–165 (2006).16517403
38. Pyke C GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody Endocrinology 2014 155 1280 1290 10.1210/en.2013-1934 24467746
Pyke, C. et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155, 1280–1290 (2014).24467746
39. Baggio LL Drucker DJ Biology of incretins: GLP-1 and GIP Gastroenterology 2007 132 2131 2157 10.1053/j.gastro.2007.03.054 17498508
Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007).17498508
40. Nauck MA Meier JJ Incretin hormones: Their role in health and disease Diab Obes. Metab. 2018 20 5 21 10.1111/dom.13129
Nauck, M. A. & Meier, J. J. Incretin hormones: Their role in health and disease. Diab Obes. Metab. 20, 5–21 (2018).
41. Ayala JE Glucagon-like peptide-1 receptor knockout mice are protected from high-fat diet-induced insulin resistance Endocrinology 2010 151 4678 4687 10.1210/en.2010-0289 20685876
Ayala, J. E. et al. Glucagon-like peptide-1 receptor knockout mice are protected from high-fat diet-induced insulin resistance. Endocrinology 151, 4678–4687 (2010).20685876
42. Ahrén B Yamada Y Seino Y The Insulin Response to Oral Glucose in GIP and GLP-1 Receptor Knockout Mice: Review of the Literature and Stepwise Glucose Dose Response Studies in Female Mice Front Endocrinol. (Lausanne) 2021 12 665537 10.3389/fendo.2021.665537 34122340
Ahrén, B., Yamada, Y. & Seino, Y. The Insulin Response to Oral Glucose in GIP and GLP-1 Receptor Knockout Mice: Review of the Literature and Stepwise Glucose Dose Response Studies in Female Mice. Front Endocrinol. (Lausanne) 12, 665537 (2021).34122340
43. Ussher JR Drucker DJ Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action Nat. Rev. Cardiol. 2023 20 463 474 10.1038/s41569-023-00849-3 36977782
Ussher, J. R. & Drucker, D. J. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat. Rev. Cardiol. 20, 463–474 (2023).36977782
44. Sheikh A Direct cardiovascular effects of glucagon like peptide-1 Diabetol. Metab. Syndr. 2013 5 47 10.1186/1758-5996-5-47 23988189
Sheikh, A. Direct cardiovascular effects of glucagon like peptide-1. Diabetol. Metab. Syndr. 5, 47 (2013).23988189
45. Zhang L Zhang W Tian X The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases Int J. Neurosci. 2023 133 473 491 10.1080/00207454.2021.1924707 33941038
Zhang, L., Zhang, W. & Tian, X. The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases. Int J. Neurosci. 133, 473–491 (2023).33941038
46. McIntyre RS The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders Behav. Brain Res 2013 237 164 171 10.1016/j.bbr.2012.09.021 23000536
McIntyre, R. S. et al. The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders. Behav. Brain Res 237, 164–171 (2013).23000536
47. Gilbert MP Pratley RE GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: Review of head-to-head clinical trials Front Endocrinol. (Lausanne) 2020 11 178 10.3389/fendo.2020.00178 32308645
Gilbert, M. P. & Pratley, R. E. GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: Review of head-to-head clinical trials. Front Endocrinol. (Lausanne) 11, 178 (2020).32308645
48. Sun, L. et al. Rational design by structural biology of industrializable, long-acting antihyperglycemic GLP-1 receptor agonists. Pharmaceuticals (Basel). 15, 740 (2022).
49. Meier JJ GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus Nat. Rev. Endocrinol. 2012 8 728 742 10.1038/nrendo.2012.140 22945360
Meier, J. J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728–742 (2012).22945360
50. Meier JJ Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes Crit. Care Med. 2004 32 848 851 10.1097/01.CCM.0000114811.60629.B5 15090972
Meier, J. J. et al. Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes. Crit. Care Med. 32, 848–851 (2004).15090972
51. Graaf C Glucagon-like peptide-1 and its class B G protein-coupled receptors: A long march to therapeutic successes Pharm. Rev. 2016 68 954 1013 10.1124/pr.115.011395 27630114
Graaf, C. et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: A long march to therapeutic successes. Pharm. Rev. 68, 954–1013 (2016).27630114
52. Furman BL The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent Toxicon 2012 59 464 471 10.1016/j.toxicon.2010.12.016 21194543
Furman, B. L. The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent. Toxicon 59, 464–471 (2012).21194543
53. Christel CM DeNardo DF Secor SM Metabolic and digestive response to food ingestion in a binge-feeding lizard, the Gila monster (Heloderma suspectum) J. Exp. Biol. 2007 210 3430 3439 10.1242/jeb.004820 17872997
Christel, C. M., DeNardo, D. F. & Secor, S. M. Metabolic and digestive response to food ingestion in a binge-feeding lizard, the Gila monster (Heloderma suspectum). J. Exp. Biol. 210, 3430–3439 (2007).17872997
54. Longwell CK Identification of N-terminally diversified GLP-1R agonists using saturation mutagenesis and chemical design ACS Chem. Biol. 2021 16 58 66 10.1021/acschembio.0c00722 33307682
Longwell, C. K. et al. Identification of N-terminally diversified GLP-1R agonists using saturation mutagenesis and chemical design. ACS Chem. Biol. 16, 58–66 (2021).33307682
55. Mapelli C Eleven amino acid glucagon-like peptide-1 receptor agonists with antidiabetic activity J. Med Chem. 2009 52 7788 7799 10.1021/jm900752a 19702274
Mapelli, C. et al. Eleven amino acid glucagon-like peptide-1 receptor agonists with antidiabetic activity. J. Med Chem. 52, 7788–7799 (2009).19702274
56. Malone J Exenatide once weekly for the treatment of type 2 diabetes Expert Opin. Investig. Drugs 2009 18 359 367 10.1517/13543780902766802 19243286
Malone, J. et al. Exenatide once weekly for the treatment of type 2 diabetes. Expert Opin. Investig. Drugs 18, 359–367 (2009).19243286
57. Gao Z Wei Y Ma G A review of recent research and development on GLP-1 receptor agonists-sustained-release microspheres J. Mater. Chem. B 2023 11 11184 11197 10.1039/D3TB02207B 37975420
Gao, Z., Wei, Y. & Ma, G. A review of recent research and development on GLP-1 receptor agonists-sustained-release microspheres. J. Mater. Chem. B 11, 11184–11197 (2023).37975420
58. Pechenov S Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease Sci. Rep. 2021 11 22521 10.1038/s41598-021-01750-0 34795324
Pechenov, S. et al. Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease. Sci. Rep. 11, 22521 (2021).34795324
59. Rasmussen MF The development of oral semaglutide, an oral GLP-1 analog, for the treatment of type 2 diabetes Diabetol. Int 2020 11 76 86 10.1007/s13340-019-00423-8 32206477
Rasmussen, M. F. The development of oral semaglutide, an oral GLP-1 analog, for the treatment of type 2 diabetes. Diabetol. Int 11, 76–86 (2020).32206477
60. Parkes DG Mace KF Trautmann ME Discovery and development of exenatide: The first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1 Expert Opin. Drug Discov. 2013 8 219 244 10.1517/17460441.2013.741580 23231438
Parkes, D. G., Mace, K. F. & Trautmann, M. E. Discovery and development of exenatide: The first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1. Expert Opin. Drug Discov. 8, 219–244 (2013).23231438
61. Andreasen CR Andersen A Knop FK Vilsbøll T Understanding the place for GLP-1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection Diab Obes. Metab. 2021 23 40 52 10.1111/dom.14500
Andreasen, C. R., Andersen, A., Knop, F. K. & Vilsbøll, T. Understanding the place for GLP-1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection. Diab Obes. Metab. 23, 40–52 (2021).
62. Drucker DJ Dritselis A Kirkpatrick P Liraglutide Nat. Rev. Drug Discov. 2010 9 267 268 10.1038/nrd3148 20357801
Drucker, D. J., Dritselis, A. & Kirkpatrick, P. Liraglutide. Nat. Rev. Drug Discov. 9, 267–268 (2010).20357801
63. National Center for Biotechnology Information. (n.d.). Lixisenatide. PubChem. Retrieved, from https://pubchem.ncbi.nlm.nih.gov/compound/Lixisenatide#section=NIPH-Clinical-Trials-Search-of-Japan (August 9, 2024).
64. Liu J Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis Bmj 2017 357 j2499 10.1136/bmj.j2499 28596247
Liu, J. et al. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. Bmj 357, j2499 (2017).28596247
65. Stewart, J. Trulicity FDA Approval History, https://www.drugs.com/history/trulicity.html (Jan 28, 2021).
66. Ozempic FDA Approval History, https://www.drugs.com/history/ozempic.html (December 5, 2017).
67. Fang X Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model Life Sci. 2021 270 118966 10.1016/j.lfs.2020.118966 33482185
Fang, X. et al. Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model. Life Sci. 270, 118966 (2021).33482185
68. Blevins T DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes J. Clin. Endocrinol. Metab. 2011 96 1301 1310 10.1210/jc.2010-2081 21307137
Blevins, T. et al. DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 96, 1301–1310 (2011).21307137
69. Faillie JL Association of bile duct and gallbladder diseases with the use of incretin-based drugs in patients with type 2 diabetes mellitus JAMA Intern Med 2016 176 1474 1481 10.1001/jamainternmed.2016.1531 27478902
Faillie, J. L. et al. Association of bile duct and gallbladder diseases with the use of incretin-based drugs in patients with type 2 diabetes mellitus. JAMA Intern Med 176, 1474–1481 (2016).27478902
70. Liu J Wang G Jia Y Xu Y GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease Diab Metab. Res. Rev. 2015 31 329 335 10.1002/dmrr.2580
Liu, J., Wang, G., Jia, Y. & Xu, Y. GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease. Diab Metab. Res. Rev. 31, 329–335 (2015).
71. McClean PL Hölscher C Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer’s disease Neuropharmacology 2014 86 241 258 10.1016/j.neuropharm.2014.07.015 25107586
McClean, P. L. & Hölscher, C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer’s disease. Neuropharmacology 86, 241–258 (2014).25107586
72. Monami M Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials Diab Res. Clin. Pr. 2014 103 269 275 10.1016/j.diabres.2014.01.010
Monami, M. et al. Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials. Diab Res. Clin. Pr. 103, 269–275 (2014).
73. Samson SL Garber A GLP-1R agonist therapy for diabetes: benefits and potential risks Curr. Opin. Endocrinol. Diab Obes. 2013 20 87 97 10.1097/MED.0b013e32835edb32
Samson, S. L. & Garber, A. GLP-1R agonist therapy for diabetes: benefits and potential risks. Curr. Opin. Endocrinol. Diab Obes. 20, 87–97 (2013).
74. Nauck M Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5) Diab Care 2014 37 2149 2158 10.2337/dc13-2761
Nauck, M. et al. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diab Care 37, 2149–2158 (2014).
75. Buse JB Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6) Lancet 2009 374 39 47 10.1016/S0140-6736(09)60659-0 19515413
Buse, J. B. et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 374, 39–47 (2009).19515413
76. Knop FK Brønden A Vilsbøll T Exenatide: pharmacokinetics, clinical use, and future directions Expert Opin. Pharmacother. 2017 18 555 571 10.1080/14656566.2017.1282463 28085521
Knop, F. K., Brønden, A. & Vilsbøll, T. Exenatide: pharmacokinetics, clinical use, and future directions. Expert Opin. Pharmacother. 18, 555–571 (2017).28085521
77. Gillian M. Keating Adis International Limited, A., New Zealand. Exenatide. ADIS DRUG PROFILE, (2005).
78. Su-yuan, C., Xiao-jing, L., & Jian-hui, L. Research progress of glucagon-like receptor agonists. Chin. J. New Drugs, 29, 2580–2585 (China, 2020).
79. Tamborlane WV Liraglutide in children and adolescents with type 2 diabetes N. Engl. J. Med. 2019 381 637 646 10.1056/NEJMoa1903822 31034184
Tamborlane, W. V. et al. Liraglutide in children and adolescents with type 2 diabetes. N. Engl. J. Med. 381, 637–646 (2019).31034184
80. O’Neil PM Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial Lancet 2018 392 637 649 10.1016/S0140-6736(18)31773-2 30122305
O’Neil, P. M. et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 392, 637–649 (2018).30122305
81. Jacobsen LV Flint A Olsen AK Ingwersen SH Liraglutide in type 2 diabetes mellitus: clinical pharmacokinetics and pharmacodynamics Clin. Pharmacokinet. 2016 55 657 672 10.1007/s40262-015-0343-6 26597252
Jacobsen, L. V., Flint, A., Olsen, A. K. & Ingwersen, S. H. Liraglutide in type 2 diabetes mellitus: clinical pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet. 55, 657–672 (2016).26597252
82. Lundgren JR Healthy weight loss maintenance with exercise, liraglutide, or both combined N. Engl. J. Med. 2021 384 1719 1730 10.1056/NEJMoa2028198 33951361
Lundgren, J. R. et al. Healthy weight loss maintenance with exercise, liraglutide, or both combined. N. Engl. J. Med. 384, 1719–1730 (2021).33951361
83. Ladenheim EE Liraglutide and obesity: a review of the data so far Drug Des. Devel Ther. 2015 9 1867 1875 10.2147/DDDT.S58459 25848222
Ladenheim, E. E. Liraglutide and obesity: a review of the data so far. Drug Des. Devel Ther. 9, 1867–1875 (2015).25848222
84. Lin CH An evaluation of liraglutide including its efficacy and safety for the treatment of obesity Expert Opin. Pharmacother. 2020 21 275 285 10.1080/14656566.2019.1695779 31790314
Lin, C. H. et al. An evaluation of liraglutide including its efficacy and safety for the treatment of obesity. Expert Opin. Pharmacother. 21, 275–285 (2020).31790314
85. Moon S Efficacy and safety of the new appetite suppressant, liraglutide: A meta-analysis of randomized controlled trials Endocrinol. Metab. (Seoul.) 2021 36 647 660 10.3803/EnM.2020.934 34139800
Moon, S. et al. Efficacy and safety of the new appetite suppressant, liraglutide: A meta-analysis of randomized controlled trials. Endocrinol. Metab. (Seoul.) 36, 647–660 (2021).34139800
86. Wilding JP Exposure-response analyses of liraglutide 3.0 mg for weight management Diab Obes. Metab. 2016 18 491 499 10.1111/dom.12639
Wilding, J. P. et al. Exposure-response analyses of liraglutide 3.0 mg for weight management. Diab Obes. Metab. 18, 491–499 (2016).
87. Yousef CC Liraglutide effects on glycemic control and weight in patients with type 2 diabetes Mellitus: A real-world, observational study and brief narrative review Diab Res Clin. Pr. 2021 177 108871 10.1016/j.diabres.2021.108871
Yousef, C. C. et al. Liraglutide effects on glycemic control and weight in patients with type 2 diabetes Mellitus: A real-world, observational study and brief narrative review. Diab Res Clin. Pr. 177, 108871 (2021).
88. Tilinca, M. C., Tiuca, R. A., Burlacu, A. & Varga, A. A 2021 update on the use of liraglutide in the modern treatment of ‘Diabesity’: A Narrative Review. Medicina (Kaunas). 57, 669 (2021).
89. Nathan DM Glycemia reduction in type 2 diabetes - microvascular and cardiovascular outcomes N. Engl. J. Med. 2022 387 1075 1088 10.1056/NEJMoa2200436 36129997
Nathan, D. M. et al. Glycemia reduction in type 2 diabetes - microvascular and cardiovascular outcomes. N. Engl. J. Med. 387, 1075–1088 (2022).36129997
90. Introduction: Standards of Medical Care in Diabetes—2022. Diabetes Care. 45, S1–S2, (United States, 2022).
91. Nathan DM Glycemia reduction in type 2 diabetes - glycemic outcomes N. Engl. J. Med. 2022 387 1063 1074 10.1056/NEJMoa2200433 36129996
Nathan, D. M. et al. Glycemia reduction in type 2 diabetes - glycemic outcomes. N. Engl. J. Med. 387, 1063–1074 (2022).36129996
92. Xie Z Efficacy and safety of liraglutide and semaglutide on weight loss in people with obesity or overweight: A systematic review Clin. Epidemiol. 2022 14 1463 1476 10.2147/CLEP.S391819 36510488
Xie, Z. et al. Efficacy and safety of liraglutide and semaglutide on weight loss in people with obesity or overweight: A systematic review. Clin. Epidemiol. 14, 1463–1476 (2022).36510488
93. Pfeffer MA Lixisenatide in patients with type 2 diabetes and acute coronary syndrome N. Engl. J. Med. 2015 373 2247 2257 10.1056/NEJMoa1509225 26630143
Pfeffer, M. A. et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373, 2247–2257 (2015).26630143
94. Christensen M Knop FK Holst JJ Vilsboll T Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus IDrugs 2009 12 503 513 19629885
Christensen, M., Knop, F. K., Holst, J. J. & Vilsboll, T. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus. IDrugs 12, 503–513 (2009).19629885
95. Xie P Pharmacokinetics and safety of Iglarlixi in healthy chinese participants: Results of a phase 1 randomized study Diab Ther. 2023 14 1387 1397 10.1007/s13300-023-01434-0
Xie, P. et al. Pharmacokinetics and safety of Iglarlixi in healthy chinese participants: Results of a phase 1 randomized study. Diab Ther. 14, 1387–1397 (2023).
96. Trujillo JM Goldman J Lixisenatide, a once-daily prandial glucagon-like peptide-1 receptor agonist for the treatment of adults with type 2 diabetes Pharmacotherapy 2017 37 927 943 10.1002/phar.1962 28556176
Trujillo, J. M. & Goldman, J. Lixisenatide, a once-daily prandial glucagon-like peptide-1 receptor agonist for the treatment of adults with type 2 diabetes. Pharmacotherapy 37, 927–943 (2017).28556176
97. Bolli GB Owens DR Lixisenatide, a novel GLP-1 receptor agonist: efficacy, safety and clinical implications for type 2 diabetes mellitus Diab Obes. Metab. 2014 16 588 601 10.1111/dom.12253
Bolli, G. B. & Owens, D. R. Lixisenatide, a novel GLP-1 receptor agonist: efficacy, safety and clinical implications for type 2 diabetes mellitus. Diab Obes. Metab. 16, 588–601 (2014).
98. Christensen M The design and discovery of lixisenatide for the treatment of type 2 diabetes mellitus Expert Opin. Drug Discov. 2014 9 1223 1251 10.1517/17460441.2014.942638 25119443
Christensen, M. et al. The design and discovery of lixisenatide for the treatment of type 2 diabetes mellitus. Expert Opin. Drug Discov. 9, 1223–1251 (2014).25119443
99. McCarty D Coleman M Boland CL Lixisenatide: A new daily GLP-1 agonist for type 2 diabetes management Ann. Pharmacother. 2017 51 401 409 10.1177/1060028017689878 28133970
McCarty, D., Coleman, M. & Boland, C. L. Lixisenatide: A new daily GLP-1 agonist for type 2 diabetes management. Ann. Pharmacother. 51, 401–409 (2017).28133970
100. Huetson P Cost-effectiveness of once daily GLP-1 receptor agonist lixisenatide compared to bolus insulin both in combination with basal insulin for the treatment of patients with type 2 diabetes in Norway J. Med. Econ. 2015 18 573 585 10.3111/13696998.2015.1038271 25853868
Huetson, P. et al. Cost-effectiveness of once daily GLP-1 receptor agonist lixisenatide compared to bolus insulin both in combination with basal insulin for the treatment of patients with type 2 diabetes in Norway. J. Med. Econ. 18, 573–585 (2015).25853868
101. Federici MO Utilization patterns of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus in Italy: A retrospective cohort study Diab Ther. 2018 9 789 801 10.1007/s13300-018-0396-2
Federici, M. O. et al. Utilization patterns of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus in Italy: A retrospective cohort study. Diab Ther. 9, 789–801 (2018).
102. Poole RM Nowlan ML Albiglutide: first global approval Drugs 2014 74 929 938 10.1007/s40265-014-0228-2 24861909
Poole, R. M. & Nowlan, M. L. Albiglutide: first global approval. Drugs 74, 929–938 (2014).24861909
103. Matthews JE Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes J. Clin. Endocrinol. Metab. 2008 93 4810 4817 10.1210/jc.2008-1518 18812476
Matthews, J. E. et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 93, 4810–4817 (2008).18812476
104. Werner U Haschke G Herling AW Kramer W Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes Regul. Pept. 2010 164 58 64 10.1016/j.regpep.2010.05.008 20570597
Werner, U., Haschke, G., Herling, A. W. & Kramer, W. Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes. Regul. Pept. 164, 58–64 (2010).20570597
105. Chang KC Comparative effectiveness of dulaglutide versus liraglutide in Asian type 2 diabetes patients: a multi-institutional cohort study and meta-analysis Cardiovasc Diabetol. 2020 19 172 10.1186/s12933-020-01148-8 33036617
Chang, K. C. et al. Comparative effectiveness of dulaglutide versus liraglutide in Asian type 2 diabetes patients: a multi-institutional cohort study and meta-analysis. Cardiovasc Diabetol. 19, 172 (2020).33036617
106. Healthcare, G. EASD 2018: the struggles of GSK’s GLP-1 receptor agonist, https://www.pharmaceutical-technology.com/comment/easd-2018-struggles-gsks-glp-1-receptor-agonist/?cf-view (October 3, 2018).
107. Pratley RE Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study Lancet Diab Endocrinol. 2014 2 289 297 10.1016/S2213-8587(13)70214-6
Pratley, R. E. et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diab Endocrinol. 2, 289–297 (2014).
108. Hoerman, J. Tanzeum (albiglutide) Discontinued After FDA Warns Of Risk Of Anaphylaxis Reaction, https://trulaw.com/fda/tanzeum-albiglutide-anaphylaxis-reaction/ (November 21, 2017).
109. Otto T Utilization patterns of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus in Germany: a retrospective cohort study Curr. Med Res Opin. 2019 35 893 901 10.1080/03007995.2018.1538011 30328731
Otto, T. et al. Utilization patterns of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus in Germany: a retrospective cohort study. Curr. Med Res Opin. 35, 893–901 (2019).30328731
110. Helfand, C. GlaxoSmithKline GLP-1 Tanzeum meets its end, and it doesn’t bode well for Sanofi, AstraZeneca: analyst, https://www.fiercepharma.com/marketing/glaxosmithkline-glp-1-tanzeum-meets-its-end-and-it-doesn-t-bode-well-for-sanofi-az (Jul 31, 2017).
111. Tanzeum® (albiglutide) – Drug discontinuation, https://professionals.optumrx.com/publications/library/drugwithdrawal-tanzeum-2017-0726.html (July 26, 2017).
112. Sanford M Dulaglutide: first global approval Drugs 2014 74 2097 2103 10.1007/s40265-014-0320-7 25367716
Sanford, M. Dulaglutide: first global approval. Drugs 74, 2097–2103 (2014).25367716
113. Tibble CA Cavaiola TS Henry RR Longer acting GLP-1 receptor agonists and the potential for improved cardiovascular outcomes: a review of current literature Expert Rev. Endocrinol. Metab. 2013 8 247 259 10.1586/eem.13.20 30780817
Tibble, C. A., Cavaiola, T. S. & Henry, R. R. Longer acting GLP-1 receptor agonists and the potential for improved cardiovascular outcomes: a review of current literature. Expert Rev. Endocrinol. Metab. 8, 247–259 (2013).30780817
114. Terauchi Y Satoi Y Takeuchi M Imaoka T Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study Endocr. J. 2014 61 949 959 10.1507/endocrj.EJ14-0147 25029955
Terauchi, Y., Satoi, Y., Takeuchi, M. & Imaoka, T. Monotherapy with the once weekly GLP-1 receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled study. Endocr. J. 61, 949–959 (2014).25029955
115. Dhillon S Semaglutide: First global approval Drugs 2018 78 275 284 10.1007/s40265-018-0871-0 29363040
Dhillon, S. Semaglutide: First global approval. Drugs 78, 275–284 (2018).29363040
116. Lau J Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide J. Med Chem. 2015 58 7370 7380 10.1021/acs.jmedchem.5b00726 26308095
Lau, J. et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J. Med Chem. 58, 7370–7380 (2015).26308095
117. Frias JP Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial Lancet 2023 402 720 730 10.1016/S0140-6736(23)01163-7 37364590
Frias, J. P. et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet 402, 720–730 (2023).37364590
118. Gao L Comparison of beinaglutide versus metformin for weight loss in overweight and obese non-diabetic patients Exp. Clin. Endocrinol. Diab 2022 130 358 367 10.1055/a-1608-0345
Gao, L. et al. Comparison of beinaglutide versus metformin for weight loss in overweight and obese non-diabetic patients. Exp. Clin. Endocrinol. Diab 130, 358–367 (2022).
119. Zhang YL Beinaglutide showed significant weight-loss benefit and effective glycaemic control for the treatment of type 2 diabetes in a real-world setting: a 3-month, multicentre, observational, retrospective, open-label study Obes. Sci. Pr. 2019 5 366 375 10.1002/osp4.342
Zhang, Y. L. et al. Beinaglutide showed significant weight-loss benefit and effective glycaemic control for the treatment of type 2 diabetes in a real-world setting: a 3-month, multicentre, observational, retrospective, open-label study. Obes. Sci. Pr. 5, 366–375 (2019).
120. Ding B Effectiveness of beinaglutide in a patient with late dumping syndrome after gastrectomy: A case report Med. (Baltim.) 2021 100 e26086 10.1097/MD.0000000000026086
Ding, B. et al. Effectiveness of beinaglutide in a patient with late dumping syndrome after gastrectomy: A case report. Med. (Baltim.) 100, e26086 (2021).
121. Aldawsari M The efficacy of GLP-1 analogues on appetite parameters, gastric emptying, food preference and taste among adults with obesity: Systematic review of randomized controlled trials Diab Metab. Syndr. Obes. 2023 16 575 595 10.2147/DMSO.S387116
Aldawsari, M. et al. The efficacy of GLP-1 analogues on appetite parameters, gastric emptying, food preference and taste among adults with obesity: Systematic review of randomized controlled trials. Diab Metab. Syndr. Obes. 16, 575–595 (2023).
122. Zhang F Recombinant human GLP-1 beinaglutide regulates lipid metabolism of adipose tissues in diet-induced obese mice iScience 2021 24 103382 10.1016/j.isci.2021.103382 34841227
Zhang, F. et al. Recombinant human GLP-1 beinaglutide regulates lipid metabolism of adipose tissues in diet-induced obese mice. iScience 24, 103382 (2021).34841227
123. Liu L Long-term cost-effectiveness of subcutaneous once-weekly semaglutide versus polyethylene glycol loxenatide for treatment of type 2 diabetes mellitus in China Diab Ther. 2023 14 93 107 10.1007/s13300-022-01336-7
Liu, L. et al. Long-term cost-effectiveness of subcutaneous once-weekly semaglutide versus polyethylene glycol loxenatide for treatment of type 2 diabetes mellitus in China. Diab Ther. 14, 93–107 (2023).
124. Nauck MA D’Alessio DA Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction Cardiovasc Diabetol. 2022 21 169 10.1186/s12933-022-01604-7 36050763
Nauck, M. A. & D’Alessio, D. A. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol. 21, 169 (2022).36050763
125. Zhou Q Efficacy and safety of tirzepatide, dual GLP-1/GIP receptor agonists, in the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials Diabetol. Metab. Syndr. 2023 15 222 10.1186/s13098-023-01198-4 37904255
Zhou, Q. et al. Efficacy and safety of tirzepatide, dual GLP-1/GIP receptor agonists, in the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetol. Metab. Syndr. 15, 222 (2023).37904255
126. Zhao F Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors Nat. Commun. 2022 13 1057 10.1038/s41467-022-28683-0 35217653
Zhao, F. et al. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat. Commun. 13, 1057 (2022).35217653
127. Brandt SJ Peptide-based multi-agonists: a new paradigm in metabolic pharmacology J. Intern Med. 2018 284 581 602 10.1111/joim.12837 30230640
Brandt, S. J. et al. Peptide-based multi-agonists: a new paradigm in metabolic pharmacology. J. Intern Med. 284, 581–602 (2018).30230640
128. Mayendraraj A Rosenkilde MM Gasbjerg LS GLP-1 and GIP receptor signaling in beta cells - A review of receptor interactions and co-stimulation Peptides 2022 151 170749 10.1016/j.peptides.2022.170749 35065096
Mayendraraj, A., Rosenkilde, M. M. & Gasbjerg, L. S. GLP-1 and GIP receptor signaling in beta cells - A review of receptor interactions and co-stimulation. Peptides 151, 170749 (2022).35065096
129. Karagiannis T Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis Diabetologia 2022 65 1251 1261 10.1007/s00125-022-05715-4 35579691
Karagiannis, T. et al. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia 65, 1251–1261 (2022).35579691
130. Fisman EZ Tenenbaum A The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect Cardiovasc Diabetol. 2021 20 225 10.1186/s12933-021-01412-5 34819089
Fisman, E. Z. & Tenenbaum, A. The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect. Cardiovasc Diabetol. 20, 225 (2021).34819089
131. Zhang Y GLP-1 receptor in pancreatic α-cells regulates glucagon secretion in a glucose-dependent bidirectional manner Diabetes 2019 68 34 44 10.2337/db18-0317 30389749
Zhang, Y. et al. GLP-1 receptor in pancreatic α-cells regulates glucagon secretion in a glucose-dependent bidirectional manner. Diabetes 68, 34–44 (2019).30389749
132. Zhang Y Erratum. GLP-1 receptor in pancreatic α-cells regulates glucagon secretion in a glucose-dependent bidirectional manner. diabetes 2019;68 Diabetes 2020 69 267 268 10.2337/db20-er02c 31843954
Zhang, Y. et al. Erratum. GLP-1 receptor in pancreatic α-cells regulates glucagon secretion in a glucose-dependent bidirectional manner. diabetes 2019;68. Diabetes 69, 267–268 (2020).31843954
133. Danowitz M De Leon DD The role of GLP-1 signaling in hypoglycemia due to hyperinsulinism Front Endocrinol. (Lausanne) 2022 13 863184 10.3389/fendo.2022.863184 35399928
Danowitz, M., & De Leon, D.D. The role of GLP-1 signaling in hypoglycemia due to hyperinsulinism. Front Endocrinol. (Lausanne) 13, 863184 (2022).35399928
134. Tong J D’Alessio D Give the receptor a brake: slowing gastric emptying by GLP-1 Diabetes 2014 63 407 409 10.2337/db13-1764 24464721
Tong, J. & D’Alessio, D. Give the receptor a brake: slowing gastric emptying by GLP-1. Diabetes 63, 407–409 (2014).24464721
135. Nogueiras R Nauck MA Tschöp MH Gut hormone co-agonists for the treatment of obesity: from bench to bedside Nat. Metab. 2023 5 933 944 10.1038/s42255-023-00812-z 37308724
Nogueiras, R., Nauck, M. A. & Tschöp, M. H. Gut hormone co-agonists for the treatment of obesity: from bench to bedside. Nat. Metab. 5, 933–944 (2023).37308724
136. Syed YY Tirzepatide: First approval Drugs 2022 82 1213 1220 10.1007/s40265-022-01746-8 35830001
Syed, Y. Y. Tirzepatide: First approval. Drugs 82, 1213–1220 (2022).35830001
137. Forzano, I. et al. Tirzepatide: A systematic update. Int. J. Mol. Sci. 23, 14631 (2022).
138. Rosenstock J Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial Lancet 2021 398 143 155 10.1016/S0140-6736(21)01324-6 34186022
Rosenstock, J. et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet 398, 143–155 (2021).34186022
139. Del Prato S Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial Lancet 2021 398 1811 1824 10.1016/S0140-6736(21)02188-7 34672967
Del Prato, S. et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 398, 1811–1824 (2021).34672967
140. Sattar N Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis Nat. Med. 2022 28 591 598 10.1038/s41591-022-01707-4 35210595
Sattar, N. et al. Tirzepatide cardiovascular event risk assessment: a pre-specified meta-analysis. Nat. Med. 28, 591–598 (2022).35210595
141. Wilson JM The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: A post hoc analysis Diab Obes. Metab. 2022 24 148 153 10.1111/dom.14553
Wilson, J. M. et al. The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: A post hoc analysis. Diab Obes. Metab. 24, 148–153 (2022).
142. France NL Syed YY Tirzepatide: A review in type 2 diabetes Drugs 2024 84 227 238 10.1007/s40265-023-01992-4 38388874
France, N. L. & Syed, Y. Y. Tirzepatide: A review in type 2 diabetes. Drugs 84, 227–238 (2024).38388874
143. Garvey WT Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial Lancet 2023 402 613 626 10.1016/S0140-6736(23)01200-X 37385275
Garvey, W. T. et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 402, 613–626 (2023).37385275
144. Romero-Gómez M A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease J. Hepatol. 2023 79 888 897 10.1016/j.jhep.2023.05.013 37355043
Romero-Gómez, M. et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J. Hepatol. 79, 888–897 (2023).37355043
145. Boland ML Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis Nat. Metab. 2020 2 413 431 10.1038/s42255-020-0209-6 32478287
Boland, M. L. et al. Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat. Metab. 2, 413–431 (2020).32478287
146. Parker VER Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes Nat. Metab. 2023 5 2086 2093 10.1038/s42255-023-00938-0 38066113
Parker, V. E. R. et al. Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes. Nat. Metab. 5, 2086–2093 (2023).38066113
147. Nahra R Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: A 54-week randomized phase 2b study Diab Care 2021 44 1433 1442 10.2337/dc20-2151
Nahra, R. et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: A 54-week randomized phase 2b study. Diab Care 44, 1433–1442 (2021).
148. Newsome PN Ambery P Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver J. Hepatol. 2023 79 1557 1565 10.1016/j.jhep.2023.07.033 37562748
Newsome, P. N. & Ambery, P. Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver. J. Hepatol. 79, 1557–1565 (2023).37562748
149. Riddy DM G protein-coupled receptors targeting insulin resistance, obesity, and type 2 diabetes mellitus Pharm. Rev. 2018 70 39 67 10.1124/pr.117.014373 29233848
Riddy, D. M. et al. G protein-coupled receptors targeting insulin resistance, obesity, and type 2 diabetes mellitus. Pharm. Rev. 70, 39–67 (2018).29233848
150. Bisson A Fauchier G Fauchier L Triple-hormone-receptor agonist retatrutide for obesity N. Engl. J. Med. 2023 389 1628 10.1056/NEJMc2310645 37888925
Bisson, A., Fauchier, G. & Fauchier, L. Triple-hormone-receptor agonist retatrutide for obesity. N. Engl. J. Med. 389, 1628 (2023).37888925
151. Knerr PJ Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice Mol. Metab. 2022 63 101533 10.1016/j.molmet.2022.101533 35809773
Knerr, P. J. et al. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol. Metab. 63, 101533 (2022).35809773
152. Liu T Ji RL Tao YX Naturally occurring mutations in G protein-coupled receptors associated with obesity and type 2 diabetes mellitus Pharm. Ther. 2022 234 108044 10.1016/j.pharmthera.2021.108044
Liu, T., Ji, R. L. & Tao, Y. X. Naturally occurring mutations in G protein-coupled receptors associated with obesity and type 2 diabetes mellitus. Pharm. Ther. 234, 108044 (2022).
153. Elfeki MA Alkhouri N Triple-hormone-receptor agonist retatrutide for obesity N. Engl. J. Med. 2023 389 1629 37888926
Elfeki, M. A. & Alkhouri, N. Triple-hormone-receptor agonist retatrutide for obesity. N. Engl. J. Med. 389, 1629 (2023).37888926
154. Urva S The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying Diab Obes. Metab. 2023 25 2784 2788 10.1111/dom.15167
Urva, S. et al. The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying. Diab Obes. Metab. 25, 2784–2788 (2023).
155. Harris E Triple-hormone combination retatrutide induces 24% body weight loss JAMA 2023 330 306 37405814
Harris, E. Triple-hormone combination retatrutide induces 24% body weight loss. JAMA 330, 306 (2023).37405814
156. Doggrell SA Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity? Expert Opin. Investig. Drugs 2023 32 355 359 10.1080/13543784.2023.2206560 37086147
Doggrell, S. A. Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity? Expert Opin. Investig. Drugs 32, 355–359 (2023).37086147
157. Urva S LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial Lancet 2022 400 1869 1881 10.1016/S0140-6736(22)02033-5 36354040
Urva, S. et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet 400, 1869–1881 (2022).36354040
158. Doggrell SA Retatrutide showing promise in obesity (and type 2 diabetes) Expert Opin. Investig. Drugs 2023 32 997 1001 10.1080/13543784.2023.2283020 37947489
Doggrell, S. A. Retatrutide showing promise in obesity (and type 2 diabetes). Expert Opin. Investig. Drugs 32, 997–1001 (2023).37947489
159. Bailey CJ Flatt PR Conlon JM Recent advances in peptide-based therapies for obesity and type 2 diabetes Peptides 2024 173 171149 10.1016/j.peptides.2024.171149 38184193
Bailey, C. J., Flatt, P. R. & Conlon, J. M. Recent advances in peptide-based therapies for obesity and type 2 diabetes. Peptides 173, 171149 (2024).38184193
160. Jastreboff AM Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial N. Engl. J. Med. 2023 389 514 526 10.1056/NEJMoa2301972 37366315
Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial. N. Engl. J. Med. 389, 514–526 (2023).37366315
161. Rosenstock J Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA Lancet 2023 402 529 544 10.1016/S0140-6736(23)01053-X 37385280
Rosenstock, J. et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet 402, 529–544 (2023).37385280
162. Abdelmalek MF A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis - Study design and rationale of HM-TRIA-201 study Contemp. Clin. Trials 2023 130 107176 10.1016/j.cct.2023.107176 37028504
Abdelmalek, M. F. et al. A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis - Study design and rationale of HM-TRIA-201 study. Contemp. Clin. Trials 130, 107176 (2023).37028504
163. Prikhodko, V. A., Bezborodkina, N. N. & Okovityi, S. V. Pharmacotherapy for non-alcoholic fatty liver disease: Emerging targets and drug candidates. Biomedicines. 10, 274 (2022).
164. Coskun, T. et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 34, 1234–1247.e1239 (2022).
165. Kaur M Misra S A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity Eur. J. Clin. Pharm. 2024 80 669 676 10.1007/s00228-024-03646-0
Kaur, M. & Misra, S. A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity. Eur. J. Clin. Pharm. 80, 669–676 (2024).
166. Baggio LL Drucker DJ Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease Mol. Metab. 2021 46 101090 10.1016/j.molmet.2020.101090 32987188
Baggio, L. L. & Drucker, D. J. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol. Metab. 46, 101090 (2021).32987188
167. Dahl D Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: The SURPASS-5 randomized clinical trial JAMA 2022 327 534 545 10.1001/jama.2022.0078 35133415
Dahl, D. et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: The SURPASS-5 randomized clinical trial. JAMA 327, 534–545 (2022).35133415
168. Frías JP Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes N. Engl. J. Med. 2021 385 503 515 10.1056/NEJMoa2107519 34170647
Frías, J. P. et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385, 503–515 (2021).34170647
169. Blaszczak, A. M., LaSalle, J. M., Concepcion, B. P. What is the pipeline for future medications for obesity? Int J Obes. (United Kingdom, 2024) 10.1038/s41366-024-01473-y.
170. Baker DE Walley K Levien TL Tirzepatide Hosp. Pharm. 2023 58 227 243 10.1177/00185787221125724 37216078
Baker, D. E., Walley, K. & Levien, T. L. Tirzepatide. Hosp. Pharm. 58, 227–243 (2023).37216078
171. Sun X Small-molecule albumin ligand modification to enhance the anti-diabetic ability of GLP-1 derivatives Biomed. Pharmacother. 2022 148 112722 10.1016/j.biopha.2022.112722 35202915
Sun, X. et al. Small-molecule albumin ligand modification to enhance the anti-diabetic ability of GLP-1 derivatives. Biomed. Pharmacother. 148, 112722 (2022).35202915
172. Saxena AR Efficacy and safety of oral small molecule glucagon-like peptide 1 receptor agonist danuglipron for glycemic control among patients with type 2 diabetes: A randomized clinical trial JAMA Netw. Open 2023 6 e2314493 10.1001/jamanetworkopen.2023.14493 37213102
Saxena, A. R. et al. Efficacy and safety of oral small molecule glucagon-like peptide 1 receptor agonist danuglipron for glycemic control among patients with type 2 diabetes: A randomized clinical trial. JAMA Netw. Open 6, e2314493 (2023).37213102
173. Nauck MA Horowitz M Non-peptide, once-per-day oral orforglipron to compete with established peptide-based, injectable GLP-1 receptor agonists Lancet 2023 402 429 431 10.1016/S0140-6736(23)01201-1 37369233
Nauck, M. A. & Horowitz, M. Non-peptide, once-per-day oral orforglipron to compete with established peptide-based, injectable GLP-1 receptor agonists. Lancet 402, 429–431 (2023).37369233
174. Wharton S Daily oral GLP-1 receptor agonist orforglipron for adults with obesity N. Engl. J. Med. 2023 389 877 888 10.1056/NEJMoa2302392 37351564
Wharton, S. et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N. Engl. J. Med. 389, 877–888 (2023).37351564
175. Therapeutics, S. Structure Therapeutics Provides Comprehensive GSBR-1290 Program Update Including Clinically Meaningful Proof-of-Concept Data From Phase 2a Clinical Study, https://ir.structuretx.com/news-releases/news-release-details/structure-therapeutics-provides-comprehensive-gsbr-1290-program (December 18, 2023).
176. Zhang T An inter-organ neural circuit for appetite suppression Cell 2022 185 2478 2494.e2428 10.1016/j.cell.2022.05.007 35662413
Zhang, T. et al. An inter-organ neural circuit for appetite suppression. Cell 185, 2478–2494.e2428 (2022).35662413
177. Sandoval DA D’Alessio DA Physiology of proglucagon peptides: Role of glucagon and GLP-1 in health and disease Physiol. Rev. 2015 95 513 548 10.1152/physrev.00013.2014 25834231
Sandoval, D. A. & D’Alessio, D. A. Physiology of proglucagon peptides: Role of glucagon and GLP-1 in health and disease. Physiol. Rev. 95, 513–548 (2015).25834231
178. Kaihara KA PKA enhances the acute insulin response leading to the restoration of glucose control Diabetes 2015 64 1688 1697 10.2337/db14-1051 25475437
Kaihara, K. A. et al. PKA enhances the acute insulin response leading to the restoration of glucose control. Diabetes 64, 1688–1697 (2015).25475437
179. Holst JJ The physiology of glucagon-like peptide 1 Physiol. Rev. 2007 87 1409 1439 10.1152/physrev.00034.2006 17928588
Holst, J. J. The physiology of glucagon-like peptide 1. Physiol. Rev. 87, 1409–1439 (2007).17928588
180. Yang H Yang L Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy J. Mol. Endocrinol. 2016 57 R93 r108 10.1530/JME-15-0316 27194812
Yang, H. & Yang, L. Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy. J. Mol. Endocrinol. 57, R93–r108 (2016).27194812
181. Hameed A Eriodictyol stimulates insulin secretion through cAMP/PKA signaling pathway in mice islets Eur. J. Pharm. 2018 820 245 255 10.1016/j.ejphar.2017.12.015
Hameed, A. et al. Eriodictyol stimulates insulin secretion through cAMP/PKA signaling pathway in mice islets. Eur. J. Pharm. 820, 245–255 (2018).
182. Almahariq M Mei FC Cheng X The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention Acta Biochim Biophys. Sin. (Shanghai) 2016 48 75 81 10.1093/abbs/gmv115 26525949
Almahariq, M., Mei, F. C. & Cheng, X. The pleiotropic role of exchange protein directly activated by cAMP 1 (EPAC1) in cancer: implications for therapeutic intervention. Acta Biochim Biophys. Sin. (Shanghai) 48, 75–81 (2016).26525949
183. Tengholm A Gylfe E cAMP signalling in insulin and glucagon secretion Diab Obes. Metab. 2017 19 42 53 10.1111/dom.12993
Tengholm, A. & Gylfe, E. cAMP signalling in insulin and glucagon secretion. Diab Obes. Metab. 19, 42–53 (2017).
184. Kaihara KA β-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion Diabetes 2013 62 1527 1536 10.2337/db12-1013 23349500
Kaihara, K. A. et al. β-Cell-specific protein kinase A activation enhances the efficiency of glucose control by increasing acute-phase insulin secretion. Diabetes 62, 1527–1536 (2013).23349500
185. Bhalla S Mehan S Khan A Rehman MU Protective role of IGF-1 and GLP-1 signaling activation in neurological dysfunctions Neurosci. Biobehav Rev. 2022 142 104896 10.1016/j.neubiorev.2022.104896 36191807
Bhalla, S., Mehan, S., Khan, A. & Rehman, M. U. Protective role of IGF-1 and GLP-1 signaling activation in neurological dysfunctions. Neurosci. Biobehav Rev. 142, 104896 (2022).36191807
186. Glauser DA Schlegel W The emerging role of FOXO transcription factors in pancreatic beta cells J. Endocrinol. 2007 193 195 207 10.1677/JOE-06-0191 17470511
Glauser, D. A. & Schlegel, W. The emerging role of FOXO transcription factors in pancreatic beta cells. J. Endocrinol. 193, 195–207 (2007).17470511
187. Purwana I GABA promotes human β-cell proliferation and modulates glucose homeostasis Diabetes 2014 63 4197 4205 10.2337/db14-0153 25008178
Purwana, I. et al. GABA promotes human β-cell proliferation and modulates glucose homeostasis. Diabetes 63, 4197–4205 (2014).25008178
188. Rondas D D’Hertog W Overbergh L Mathieu C Glucagon-like peptide-1: modulator of β-cell dysfunction and death Diab Obes. Metab. 2013 15 185 192 10.1111/dom.12165
Rondas, D., D’Hertog, W., Overbergh, L. & Mathieu, C. Glucagon-like peptide-1: modulator of β-cell dysfunction and death. Diab Obes. Metab. 15, 185–192 (2013).
189. Ahrén B Hepato-incretin function of GLP-1: novel concept and target in type 1 diabetes Diabetes 2015 64 715 717 10.2337/db14-1671 25713199
Ahrén, B. Hepato-incretin function of GLP-1: novel concept and target in type 1 diabetes. Diabetes 64, 715–717 (2015).25713199
190. Jun LS Absence of glucagon and insulin action reveals a role for the GLP-1 receptor in endogenous glucose production Diabetes 2015 64 819 827 10.2337/db14-1052 25288673
Jun, L. S. et al. Absence of glucagon and insulin action reveals a role for the GLP-1 receptor in endogenous glucose production. Diabetes 64, 819–827 (2015).25288673
191. Holter MM Saikia M Cummings BP Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion Front Endocrinol. (Lausanne) 2022 13 934775 10.3389/fendo.2022.934775 35957816
Holter, M. M., Saikia, M. & Cummings, B. P. Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion. Front Endocrinol. (Lausanne) 13, 934775 (2022).35957816
192. Saraiva FK Sposito AC Cardiovascular effects of glucagon-like peptide 1 (GLP-1) receptor agonists Cardiovasc Diabetol. 2014 13 142 10.1186/s12933-014-0142-7 25338737
Saraiva, F. K. & Sposito, A. C. Cardiovascular effects of glucagon-like peptide 1 (GLP-1) receptor agonists. Cardiovasc Diabetol. 13, 142 (2014).25338737
193. Lucey M Acylation of the incretin peptide exendin-4 directly impacts glucagon-like peptide-1 receptor signaling and trafficking Mol. Pharm. 2021 100 319 334 10.1124/molpharm.121.000270
Lucey, M. et al. Acylation of the incretin peptide exendin-4 directly impacts glucagon-like peptide-1 receptor signaling and trafficking. Mol. Pharm. 100, 319–334 (2021).
194. Deganutti G Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation Nat. Commun. 2022 13 92 10.1038/s41467-021-27760-0 35013280
Deganutti, G. et al. Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation. Nat. Commun. 13, 92 (2022).35013280
195. Ma H Structural insights into the activation of GLP-1R by a small molecule agonist Cell Res. 2020 30 1140 1142 10.1038/s41422-020-0384-8 32724086
Ma, H. et al. Structural insights into the activation of GLP-1R by a small molecule agonist. Cell Res. 30, 1140–1142 (2020).32724086
196. Cong Z Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with G(s) proteins Cell Discov. 2024 10 18 10.1038/s41421-024-00649-0 38346960
Cong, Z. et al. Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with G(s) proteins. Cell Discov. 10, 18 (2024).38346960
197. Liu TM OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells Blood 2015 125 284 295 10.1182/blood-2014-06-583518 25293770
Liu, T. M. et al. OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells. Blood 125, 284–295 (2015).25293770
198. Liu, P., Wang, Z. & Wei, W. Phosphorylation of Akt at the C-terminal tail triggers Akt activation. Cell Cycle 13, 1947–1955 (2014).
199. Chan CH Posttranslational regulation of Akt in human cancer Cell Biosci. 2014 4 59 10.1186/2045-3701-4-59 25309720
Chan, C. H. et al. Posttranslational regulation of Akt in human cancer. Cell Biosci. 4, 59 (2014).25309720
200. van Dam EM Govers R James DE Akt activation is required at a late stage of insulin-induced GLUT4 translocation to the plasma membrane Mol. Endocrinol. 2005 19 1067 1077 10.1210/me.2004-0413 15650020
van Dam, E. M., Govers, R. & James, D. E. Akt activation is required at a late stage of insulin-induced GLUT4 translocation to the plasma membrane. Mol. Endocrinol. 19, 1067–1077 (2005).15650020
201. Chang YC Glucose transporter 4: Insulin response mastermind, glycolysis catalyst and treatment direction for cancer progression Cancer Lett. 2023 563 216179 10.1016/j.canlet.2023.216179 37061122
Chang, Y. C. et al. Glucose transporter 4: Insulin response mastermind, glycolysis catalyst and treatment direction for cancer progression. Cancer Lett. 563, 216179 (2023).37061122
202. Gao Y Effects of D-pinitol on insulin resistance through the PI3K/Akt signaling pathway in type 2 diabetes mellitus rats J. Agric Food Chem. 2015 63 6019 6026 10.1021/acs.jafc.5b01238 26063468
Gao, Y. et al. Effects of D-pinitol on insulin resistance through the PI3K/Akt signaling pathway in type 2 diabetes mellitus rats. J. Agric Food Chem. 63, 6019–6026 (2015).26063468
203. Yang F Knockdown of NCAPD3 inhibits the tumorigenesis of non-small cell lung cancer by regulation of the PI3K/Akt pathway BMC Cancer 2024 24 408 10.1186/s12885-024-12131-x 38566039
Yang, F. et al. Knockdown of NCAPD3 inhibits the tumorigenesis of non-small cell lung cancer by regulation of the PI3K/Akt pathway. BMC Cancer 24, 408 (2024).38566039
204. García S Liz M Gómez-Reino JJ Conde C Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibition of Bid cleavage Arthritis Res Ther. 2010 12 R33 10.1186/ar2941 20187936
García, S., Liz, M., Gómez-Reino, J. J. & Conde, C. Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibition of Bid cleavage. Arthritis Res Ther. 12, R33 (2010).20187936
205. Cignarelli A Mini review: Effect of GLP-1 receptor agonists and SGLT-2 inhibitors on the growth hormone/IGF axis Front Endocrinol. (Lausanne) 2022 13 846903 10.3389/fendo.2022.846903 35265043
Cignarelli, A. et al. Mini review: Effect of GLP-1 receptor agonists and SGLT-2 inhibitors on the growth hormone/IGF axis. Front Endocrinol. (Lausanne) 13, 846903 (2022).35265043
206. Rowlands J Heng J Newsholme P Carlessi R PleiOTROPIC EFFects of GLP-1 and analogs on cell signaling, metabolism, and function Front Endocrinol. (Lausanne) 2018 9 672 10.3389/fendo.2018.00672 30532733
Rowlands, J., Heng, J., Newsholme, P. & Carlessi, R. PleiOTROPIC EFFects of GLP-1 and analogs on cell signaling, metabolism, and function. Front Endocrinol. (Lausanne) 9, 672 (2018).30532733
207. Chai W Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism Diabetes 2012 61 888 896 10.2337/db11-1073 22357961
Chai, W. et al. Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes 61, 888–896 (2012).22357961
208. Andreozzi F The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism J. Transl. Med. 2016 14 229 10.1186/s12967-016-0985-7 27473212
Andreozzi, F. et al. The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. J. Transl. Med. 14, 229 (2016).27473212
209. Jiang Y GLP-1 improves adipocyte insulin sensitivity following induction of endoplasmic reticulum stress Front Pharm. 2018 9 1168 10.3389/fphar.2018.01168
Jiang, Y. et al. GLP-1 improves adipocyte insulin sensitivity following induction of endoplasmic reticulum stress. Front Pharm. 9, 1168 (2018).
210. Singh I Activation of arcuate nucleus glucagon-like peptide-1 receptor-expressing neurons suppresses food intake Cell Biosci. 2022 12 178 10.1186/s13578-022-00914-3 36309763
Singh, I. et al. Activation of arcuate nucleus glucagon-like peptide-1 receptor-expressing neurons suppresses food intake. Cell Biosci. 12, 178 (2022).36309763
211. Baggio LL Drucker DJ Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight J. Clin. Invest 2014 124 4223 4226 10.1172/JCI78371 25202976
Baggio, L. L. & Drucker, D. J. Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight. J. Clin. Invest 124, 4223–4226 (2014).25202976
212. van Bloemendaal L GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans Diabetes 2014 63 4186 4196 10.2337/db14-0849 25071023
van Bloemendaal, L. et al. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 63, 4186–4196 (2014).25071023
213. Barakat GM Ramadan W Assi G Khoury NBE Satiety: a gut-brain-relationship J. Physiol. Sci. 2024 74 11 10.1186/s12576-024-00904-9 38368346
Barakat, G. M., Ramadan, W., Assi, G. & Khoury, N. B. E. Satiety: a gut-brain-relationship. J. Physiol. Sci. 74, 11 (2024).38368346
214. Nachawi N Rao PP Makin V The role of GLP-1 receptor agonists in managing type 2 diabetes Cleve Clin. J. Med 2022 89 457 464 10.3949/ccjm.89a.21110 35914933
Nachawi, N., Rao, P. P. & Makin, V. The role of GLP-1 receptor agonists in managing type 2 diabetes. Cleve Clin. J. Med 89, 457–464 (2022).35914933
215. Iqbal J Effect of glucagon-like peptide-1 receptor agonists on body weight in adults with obesity without diabetes mellitus-a systematic review and meta-analysis of randomized control trials Obes. Rev. 2022 23 e13435 10.1111/obr.13435 35194917
Iqbal, J. et al. Effect of glucagon-like peptide-1 receptor agonists on body weight in adults with obesity without diabetes mellitus-a systematic review and meta-analysis of randomized control trials. Obes. Rev. 23, e13435 (2022).35194917
216. Lee YS Glucagon-like peptide 1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation Diabetes 2018 67 2601 2614 10.2337/db18-0155 30257975
Lee, Y. S. et al. Glucagon-like peptide 1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation. Diabetes 67, 2601–2614 (2018).30257975
217. Wei R Antagonistic glucagon receptor antibody promotes α-cell proliferation and increases β-cell mass in diabetic mice iScience 2019 16 326 339 10.1016/j.isci.2019.05.030 31203188
Wei, R. et al. Antagonistic glucagon receptor antibody promotes α-cell proliferation and increases β-cell mass in diabetic mice. iScience 16, 326–339 (2019).31203188
218. Drucker DJ Glucagon-like peptide-1 and the islet beta-cell: augmentation of cell proliferation and inhibition of apoptosis Endocrinology 2003 144 5145 5148 10.1210/en.2003-1147 14645210
Drucker, D. J. Glucagon-like peptide-1 and the islet beta-cell: augmentation of cell proliferation and inhibition of apoptosis. Endocrinology 144, 5145–5148 (2003).14645210
219. Miki T Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility Diabetes 2005 54 1056 1063 10.2337/diabetes.54.4.1056 15793244
Miki, T. et al. Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility. Diabetes 54, 1056–1063 (2005).15793244
220. Holz GG Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell Diabetes 2004 53 5 13 10.2337/diabetes.53.1.5 14693691
Holz, G. G. Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell. Diabetes 53, 5–13 (2004).14693691
221. Naylor J Use of CRISPR/Cas9-engineered INS-1 pancreatic β cells to define the pharmacology of dual GIPR/GLP-1R agonists Biochem J. 2016 473 2881 2891 10.1042/BCJ20160476 27422784
Naylor, J. et al. Use of CRISPR/Cas9-engineered INS-1 pancreatic β cells to define the pharmacology of dual GIPR/GLP-1R agonists. Biochem J. 473, 2881–2891 (2016).27422784
222. Pamir N Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis Am. J. Physiol. Endocrinol. Metab. 2003 284 E931 939 10.1152/ajpendo.00270.2002 12540373
Pamir, N. et al. Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis. Am. J. Physiol. Endocrinol. Metab. 284, E931–939 (2003).12540373
223. Koppes EA Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones PLoS Genet 2023 19 e1010710 10.1371/journal.pgen.1010710 37068109
Koppes, E. A. et al. Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones. PLoS Genet 19, e1010710 (2023).37068109
224. Kim SJ Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression J. Biol. Chem. 2005 280 22297 22307 10.1074/jbc.M500540200 15817464
Kim, S. J. et al. Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. J. Biol. Chem. 280, 22297–22307 (2005).15817464
225. Wei T Glucagon acting at the GLP-1 receptor contributes to β-cell regeneration induced by glucagon receptor antagonism in diabetic mice Diabetes 2023 72 599 610 10.2337/db22-0784 36826938
Wei, T. et al. Glucagon acting at the GLP-1 receptor contributes to β-cell regeneration induced by glucagon receptor antagonism in diabetic mice. Diabetes 72, 599–610 (2023).36826938
226. Gotoh K Hypothalamic brain-derived neurotrophic factor regulates glucagon secretion mediated by pancreatic efferent nerves J. Neuroendocrinol. 2013 25 302 311 10.1111/jne.12003 23157205
Gotoh, K. et al. Hypothalamic brain-derived neurotrophic factor regulates glucagon secretion mediated by pancreatic efferent nerves. J. Neuroendocrinol. 25, 302–311 (2013).23157205
227. Qiao L Maternal GLP-1 receptor activation inhibits fetal growth Am. J. Physiol. Endocrinol. Metab. 2024 326 E268 e276 10.1152/ajpendo.00361.2023 38197791
Qiao, L. et al. Maternal GLP-1 receptor activation inhibits fetal growth. Am. J. Physiol. Endocrinol. Metab. 326, E268–e276 (2024).38197791
228. Chou CL Collecting duct water permeability inhibition by EGF is associated with decreased cAMP, PKA activity, and AQP2 phosphorylation at Ser(269) Am. J. Physiol. Ren. Physiol. 2024 326 F545 f559 10.1152/ajprenal.00197.2023
Chou, C. L. et al. Collecting duct water permeability inhibition by EGF is associated with decreased cAMP, PKA activity, and AQP2 phosphorylation at Ser(269). Am. J. Physiol. Ren. Physiol. 326, F545–f559 (2024).
229. Planès C Hypoxia and beta 2-agonists regulate cell surface expression of the epithelial sodium channel in native alveolar epithelial cells J. Biol. Chem. 2002 277 47318 47324 10.1074/jbc.M209158200 12372821
Planès, C. et al. Hypoxia and beta 2-agonists regulate cell surface expression of the epithelial sodium channel in native alveolar epithelial cells. J. Biol. Chem. 277, 47318–47324 (2002).12372821
230. Eaton M Hernandez LA Schaefer S Ischemic preconditioning and diazoxide limit mitochondrial Ca overload during ischemia/reperfusion: Role of reactive oxygen species Exp. Clin. Cardiol. 2005 10 96 103 19641667
Eaton, M., Hernandez, L. A. & Schaefer, S. Ischemic preconditioning and diazoxide limit mitochondrial Ca overload during ischemia/reperfusion: Role of reactive oxygen species. Exp. Clin. Cardiol. 10, 96–103 (2005).19641667
231. Wang L Preconditioning limits mitochondrial Ca(2+) during ischemia in rat hearts: Role of K(ATP) channels Am. J. Physiol. Heart Circ. Physiol. 2001 280 H2321 2328 10.1152/ajpheart.2001.280.5.H2321 11299237
Wang, L. et al. Preconditioning limits mitochondrial Ca(2+) during ischemia in rat hearts: Role of K(ATP) channels. Am. J. Physiol. Heart Circ. Physiol. 280, H2321–2328 (2001).11299237
232. Bagger JI Glucagonostatic potency of GLP-1 in patients with type 2 diabetes, patients with type 1 diabetes, and healthy control subjects Diabetes 2021 70 1347 1356 10.2337/db20-0998 33722838
Bagger, J. I. et al. Glucagonostatic potency of GLP-1 in patients with type 2 diabetes, patients with type 1 diabetes, and healthy control subjects. Diabetes 70, 1347–1356 (2021).33722838
233. Lebrun LJ Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion Cell Rep. 2017 21 1160 1168 10.1016/j.celrep.2017.10.008 29091756
Lebrun, L. J. et al. Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion. Cell Rep. 21, 1160–1168 (2017).29091756
234. Ramracheya R GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca(2+) channels Physiol. Rep. 2018 6 e13852 10.14814/phy2.13852 30187652
Ramracheya, R. et al. GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca(2+) channels. Physiol. Rep. 6, e13852 (2018).30187652
235. De Marinis YZ GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis Cell Metab. 2010 11 543 553 10.1016/j.cmet.2010.04.007 20519125
De Marinis, Y. Z. et al. GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis. Cell Metab. 11, 543–553 (2010).20519125
236. Andreu JM Carreira J Muñoz E Isolation and partial characterization of the two major subunits of the BF1 factor (ATPase) from Micrococcus lysodeikticus and evidence for their glycoprotein nature FEBS Lett. 1976 65 198 203 10.1016/0014-5793(76)80479-6 6334
Andreu, J. M., Carreira, J. & Muñoz, E. Isolation and partial characterization of the two major subunits of the BF1 factor (ATPase) from Micrococcus lysodeikticus and evidence for their glycoprotein nature. FEBS Lett. 65, 198–203 (1976).6334
237. Aird I Intestinal obstruction : The results of recent experiment applied to clinical practice Edinb. Med J. 1936 43 375 394 29646985
Aird, I. Intestinal obstruction : The results of recent experiment applied to clinical practice. Edinb. Med J. 43, 375–394 (1936).29646985
238. Saltiel AR Kahn CR Insulin signalling and the regulation of glucose and lipid metabolism Nature 2001 414 799 806 10.1038/414799a 11742412
Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).11742412
239. Meier JJ Nauck MA Glucagon-like peptide 1(GLP-1) in biology and pathology Diab Metab. Res. Rev. 2005 21 91 117 10.1002/dmrr.538
Meier, J. J. & Nauck, M. A. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diab Metab. Res. Rev. 21, 91–117 (2005).
240. Marathe CS Rayner CK Jones KL Horowitz M Relationships between gastric emptying, postprandial glycemia, and incretin hormones Diab Care 2013 36 1396 1405 10.2337/dc12-1609
Marathe, C. S., Rayner, C. K., Jones, K. L. & Horowitz, M. Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diab Care 36, 1396–1405 (2013).
241. Gandasi NR GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion Diabetologia 2024 67 528 546 10.1007/s00125-023-06060-w 38127123
Gandasi, N. R. et al. GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion. Diabetologia 67, 528–546 (2024).38127123
242. Heller RS Kieffer TJ Habener JF Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas Diabetes 1997 46 785 791 10.2337/diab.46.5.785 9133545
Heller, R. S., Kieffer, T. J. & Habener, J. F. Insulinotropic glucagon-like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas. Diabetes 46, 785–791 (1997).9133545
243. Brereton MF Vergari E Zhang Q Clark A Alpha-, Delta- and PP-cells: are they the architectural cornerstones of islet structure and co-ordination? J. Histochem Cytochem 2015 63 575 591 10.1369/0022155415583535 26216135
Brereton, M. F., Vergari, E., Zhang, Q. & Clark, A. Alpha-, Delta- and PP-cells: are they the architectural cornerstones of islet structure and co-ordination? J. Histochem Cytochem 63, 575–591 (2015).26216135
244. Hauge-Evans AC Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function Diabetes 2009 58 403 411 10.2337/db08-0792 18984743
Hauge-Evans, A. C. et al. Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58, 403–411 (2009).18984743
245. Pappas TN Debas HT Goto Y Taylor IL Peptide YY inhibits meal-stimulated pancreatic and gastric secretion Am. J. Physiol. 1985 248 G118 123 3838121
Pappas, T. N., Debas, H. T., Goto, Y. & Taylor, I. L. Peptide YY inhibits meal-stimulated pancreatic and gastric secretion. Am. J. Physiol. 248, G118–123 (1985).3838121
246. Brazeau P Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone Science 1973 179 77 79 10.1126/science.179.4068.77 4682131
Brazeau, P. et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179, 77–79 (1973).4682131
247. Gromada J Holst JJ Rorsman P Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1 Pflug. Arch. 1998 435 583 594 10.1007/s004240050558
Gromada, J., Holst, J. J. & Rorsman, P. Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflug. Arch. 435, 583–594 (1998).
248. Shilleh AH GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells Peptides 2024 175 171179 10.1016/j.peptides.2024.171179 38360354
Shilleh, A. H. et al. GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells. Peptides 175, 171179 (2024).38360354
249. Rutter GA Regulating glucagon secretion: somatostatin in the spotlight Diabetes 2009 58 299 301 10.2337/db08-1534 19171745
Rutter, G. A. Regulating glucagon secretion: somatostatin in the spotlight. Diabetes 58, 299–301 (2009).19171745
250. Strowski MZ Parmar RM Blake AD Schaeffer JM Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice Endocrinology 2000 141 111 117 10.1210/endo.141.1.7263 10614629
Strowski, M. Z., Parmar, R. M., Blake, A. D. & Schaeffer, J. M. Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology 141, 111–117 (2000).10614629
251. Ørgaard A Holst JJ The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice Diabetologia 2017 60 1731 1739 10.1007/s00125-017-4315-2 28551699
Ørgaard, A. & Holst, J. J. The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice. Diabetologia 60, 1731–1739 (2017).28551699
252. Gao, R., Yang, T. & Zhang, Q. δ-Cells: The neighborhood watch in the islet community. Biology (Basel). 10, 74 (2021).
253. Röder PV Wu B Liu Y Han W Pancreatic regulation of glucose homeostasis Exp. Mol. Med. 2016 48 e219 10.1038/emm.2016.6 26964835
Röder, P. V., Wu, B., Liu, Y. & Han, W. Pancreatic regulation of glucose homeostasis. Exp. Mol. Med. 48, e219 (2016).26964835
254. Garzilli I Itzkovitz S Design principles of the paradoxical feedback between pancreatic alpha and beta cells Sci. Rep. 2018 8 10694 10.1038/s41598-018-29084-4 30013127
Garzilli, I. & Itzkovitz, S. Design principles of the paradoxical feedback between pancreatic alpha and beta cells. Sci. Rep. 8, 10694 (2018).30013127
255. Donnelly D The structure and function of the glucagon-like peptide-1 receptor and its ligands Br. J. Pharm. 2012 166 27 41 10.1111/j.1476-5381.2011.01687.x
Donnelly, D. The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br. J. Pharm. 166, 27–41 (2012).
256. Mentlein R Gallwitz B Schmidt WE Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum Eur. J. Biochem 1993 214 829 835 10.1111/j.1432-1033.1993.tb17986.x 8100523
Mentlein, R., Gallwitz, B. & Schmidt, W. E. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem 214, 829–835 (1993).8100523
257. Kieffer TJ McIntosh CH Pederson RA Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV Endocrinology 1995 136 3585 3596 10.1210/endo.136.8.7628397 7628397
Kieffer, T. J., McIntosh, C. H. & Pederson, R. A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136, 3585–3596 (1995).7628397
258. Knudsen LB Pridal L Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor Eur. J. Pharm. 1996 318 429 435 10.1016/S0014-2999(96)00795-9
Knudsen, L. B. & Pridal, L. Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor. Eur. J. Pharm. 318, 429–435 (1996).
259. Patel D Glycaemic and non-glycaemic efficacy of once-weekly GLP-1 receptor agonists in people with type 2 diabetes J. Clin. Pharm. Ther. 2020 45 28 42 10.1111/jcpt.13224 32910489
Patel, D. Glycaemic and non-glycaemic efficacy of once-weekly GLP-1 receptor agonists in people with type 2 diabetes. J. Clin. Pharm. Ther. 45, 28–42 (2020).32910489
260. Meyer-Gerspach AC Endogenous GLP-1 alters postprandial functional connectivity between homeostatic and reward-related brain regions involved in regulation of appetite in healthy lean males: A pilotstudy Diab Obes. Metab. 2018 20 2330 2338 10.1111/dom.13369
Meyer-Gerspach, A. C. et al. Endogenous GLP-1 alters postprandial functional connectivity between homeostatic and reward-related brain regions involved in regulation of appetite in healthy lean males: A pilotstudy. Diab Obes. Metab. 20, 2330–2338 (2018).
261. Phillips A Clements JN Clinical review of subcutaneous semaglutide for obesity J. Clin. Pharm. Ther. 2022 47 184 193 10.1111/jcpt.13574 34964141
Phillips, A. & Clements, J. N. Clinical review of subcutaneous semaglutide for obesity. J. Clin. Pharm. Ther. 47, 184–193 (2022).34964141
262. Ando H Glucagon-like peptide-1 reduces pancreatic β-cell mass through hypothalamic neural pathways in high-fat diet-induced obese rats Sci. Rep. 2017 7 5578 10.1038/s41598-017-05371-4 28717164
Ando, H. et al. Glucagon-like peptide-1 reduces pancreatic β-cell mass through hypothalamic neural pathways in high-fat diet-induced obese rats. Sci. Rep. 7, 5578 (2017).28717164
263. Yamanaka M Protective effect of brain-derived neurotrophic factor on pancreatic islets in obese diabetic mice Metabolism 2006 55 1286 1292 10.1016/j.metabol.2006.04.017 16979397
Yamanaka, M. et al. Protective effect of brain-derived neurotrophic factor on pancreatic islets in obese diabetic mice. Metabolism 55, 1286–1292 (2006).16979397
264. Edholm T Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis Neurogastroenterol. Motil. 2010 22 1191 1200.e1315 10.1111/j.1365-2982.2010.01554.x 20584260
Edholm, T. et al. Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis. Neurogastroenterol. Motil. 22, 1191–1200.e1315 (2010).20584260
265. van Bloemendaal L Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans Diab Obes. Metab. 2015 17 878 886 10.1111/dom.12506
van Bloemendaal, L. et al. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans. Diab Obes. Metab. 17, 878–886 (2015).
266. Papaconstantinou I The impact of peri-operative anti-TNF treatment on anastomosis-related complications in Crohn’s disease patients. A critical review J. Gastrointest. Surg. 2014 18 1216 1224 10.1007/s11605-014-2487-3 24599780
Papaconstantinou, I. et al. The impact of peri-operative anti-TNF treatment on anastomosis-related complications in Crohn’s disease patients. A critical review. J. Gastrointest. Surg. 18, 1216–1224 (2014).24599780
267. Farr OM GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial Diabetologia 2016 59 954 965 10.1007/s00125-016-3874-y 26831302
Farr, O. M. et al. GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. Diabetologia 59, 954–965 (2016).26831302
268. Nauck MA Kemmeries G Holst JJ Meier JJ Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans Diabetes 2011 60 1561 1565 10.2337/db10-0474 21430088
Nauck, M. A., Kemmeries, G., Holst, J. J. & Meier, J. J. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 60, 1561–1565 (2011).21430088
269. Little TJ Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses J. Clin. Endocrinol. Metab. 2006 91 1916 1923 10.1210/jc.2005-2220 16492694
Little, T. J. et al. Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses. J. Clin. Endocrinol. Metab. 91, 1916–1923 (2006).16492694
270. Moran TH McHugh PR Cholecystokinin suppresses food intake by inhibiting gastric emptying Am. J. Physiol. 1982 242 R491 497 7081475
Moran, T. H. & McHugh, P. R. Cholecystokinin suppresses food intake by inhibiting gastric emptying. Am. J. Physiol. 242, R491–497 (1982).7081475
271. Robinson PH McHugh PR Moran TH Stephenson JD Gastric control of food intake J. Psychosom. Res. 1988 32 593 606 10.1016/0022-3999(88)90008-6 3065484
Robinson, P. H., McHugh, P. R., Moran, T. H. & Stephenson, J. D. Gastric control of food intake. J. Psychosom. Res. 32, 593–606 (1988).3065484
272. Tahrani A Morton J Benefits of weight loss of 10% or more in patients with overweight or obesity: A review Obesity 2022 30 802 840 10.1002/oby.23371 35333446
Tahrani, A. & Morton, J. Benefits of weight loss of 10% or more in patients with overweight or obesity: A review. Obesity 30, 802–840 (2022).35333446
273. Chen J Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat Cell Death Dis. 2018 9 212 10.1038/s41419-017-0217-y 29434185
Chen, J. et al. Glucagon-like peptide-1 receptor regulates endoplasmic reticulum stress-induced apoptosis and the associated inflammatory response in chondrocytes and the progression of osteoarthritis in rat. Cell Death Dis. 9, 212 (2018).29434185
274. Bjørnholm KD Activation of the renal GLP-1R leads to expression of Ren1 in the renal vascular tree Endocrinol. Diab Metab. 2021 4 e00234 10.1002/edm2.234
Bjørnholm, K. D. et al. Activation of the renal GLP-1R leads to expression of Ren1 in the renal vascular tree. Endocrinol. Diab Metab. 4, e00234 (2021).
275. Foer D Glucagon-like peptide-1 receptor pathway attenuates platelet activation in aspirin-exacerbated respiratory disease J. Immunol. 2023 211 1806 1813 10.4049/jimmunol.2300102 37870292
Foer, D. et al. Glucagon-like peptide-1 receptor pathway attenuates platelet activation in aspirin-exacerbated respiratory disease. J. Immunol. 211, 1806–1813 (2023).37870292
276. Loeser RF Collins JA Diekman BO Ageing and the pathogenesis of osteoarthritis Nat. Rev. Rheumatol. 2016 12 412 420 10.1038/nrrheum.2016.65 27192932
Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 412–420 (2016).27192932
277. Aigner T Haag J Martin J Buckwalter J Osteoarthritis: Aging of matrix and cells–going for a remedy Curr. Drug Targets 2007 8 325 331 10.2174/138945007779940070 17305510
Aigner, T., Haag, J., Martin, J. & Buckwalter, J. Osteoarthritis: Aging of matrix and cells–going for a remedy. Curr. Drug Targets 8, 325–331 (2007).17305510
278. Wang X Fisetin suppresses chondrocyte senescence and attenuates osteoarthritis progression by targeting sirtuin 6 Chem. Biol. Interact. 2024 390 110890 10.1016/j.cbi.2024.110890 38278314
Wang, X. et al. Fisetin suppresses chondrocyte senescence and attenuates osteoarthritis progression by targeting sirtuin 6. Chem. Biol. Interact. 390, 110890 (2024).38278314
279. Shiraishi D Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation Biochem Biophys. Res Commun. 2012 425 304 308 10.1016/j.bbrc.2012.07.086 22842565
Shiraishi, D. et al. Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation. Biochem Biophys. Res Commun. 425, 304–308 (2012).22842565
280. Noguchi T The GLP-1 receptor agonist exenatide improves recovery from spinal cord injury by inducing macrophage polarization toward the M2 phenotype Front Neurosci. 2024 18 1342944 10.3389/fnins.2024.1342944 38426018
Noguchi, T. et al. The GLP-1 receptor agonist exenatide improves recovery from spinal cord injury by inducing macrophage polarization toward the M2 phenotype. Front Neurosci. 18, 1342944 (2024).38426018
281. Que Q The GLP-1 agonist, liraglutide, ameliorates inflammation through the activation of the PKA/CREB pathway in a rat model of knee osteoarthritis J. Inflamm. (Lond.) 2019 16 13 10.1186/s12950-019-0218-y 31182934
Que, Q. et al. The GLP-1 agonist, liraglutide, ameliorates inflammation through the activation of the PKA/CREB pathway in a rat model of knee osteoarthritis. J. Inflamm. (Lond.) 16, 13 (2019).31182934
282. Fernandes TL Macrophage: A potential target on cartilage regeneration Front Immunol. 2020 11 111 10.3389/fimmu.2020.00111 32117263
Fernandes, T. L. et al. Macrophage: A potential target on cartilage regeneration. Front Immunol. 11, 111 (2020).32117263
283. Sun AR Is synovial macrophage activation the inflammatory link between obesity and osteoarthritis? Curr. Rheumatol. Rep. 2016 18 57 10.1007/s11926-016-0605-9 27422277
Sun, A. R. et al. Is synovial macrophage activation the inflammatory link between obesity and osteoarthritis? Curr. Rheumatol. Rep. 18, 57 (2016).27422277
284. Sanchez-Lopez E Synovial inflammation in osteoarthritis progression Nat. Rev. Rheumatol. 2022 18 258 275 10.1038/s41584-022-00749-9 35165404
Sanchez-Lopez, E. et al. Synovial inflammation in osteoarthritis progression. Nat. Rev. Rheumatol. 18, 258–275 (2022).35165404
285. Kapoor M Role of proinflammatory cytokines in the pathophysiology of osteoarthritis Nat. Rev. Rheumatol. 2011 7 33 42 10.1038/nrrheum.2010.196 21119608
Kapoor, M. et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat. Rev. Rheumatol. 7, 33–42 (2011).21119608
286. Wang T He C Pro-inflammatory cytokines: The link between obesity and osteoarthritis Cytokine Growth Factor Rev. 2018 44 38 50 10.1016/j.cytogfr.2018.10.002 30340925
Wang, T. & He, C. Pro-inflammatory cytokines: The link between obesity and osteoarthritis. Cytokine Growth Factor Rev. 44, 38–50 (2018).30340925
287. Chang SY Exendin-4 inhibits iNOS expression at the protein level in LPS-stimulated Raw264.7 macrophage by the activation of cAMP/PKA pathway J. Cell Biochem 2013 114 844 853 10.1002/jcb.24425 23097217
Chang, S. Y. et al. Exendin-4 inhibits iNOS expression at the protein level in LPS-stimulated Raw264.7 macrophage by the activation of cAMP/PKA pathway. J. Cell Biochem 114, 844–853 (2013).23097217
288. Kang JH Exendin-4 inhibits interleukin-1beta-induced iNOS expression at the protein level, but not at the transcriptional and posttranscriptional levels, in RINm5F beta-cells J. Endocrinol. 2009 202 65 75 10.1677/JOE-08-0507 19398497
Kang, J. H. et al. Exendin-4 inhibits interleukin-1beta-induced iNOS expression at the protein level, but not at the transcriptional and posttranscriptional levels, in RINm5F beta-cells. J. Endocrinol. 202, 65–75 (2009).19398497
289. Liu, N., Wang, Y., Li, T. & Feng, X. G-Protein Coupled Receptors (GPCRs): Signaling Pathways, Characterization, and Functions in Insect Physiology and Toxicology. Int. J. Mol. Sci. 22, 5260 (2021).
290. Weivoda MM Wnt signaling inhibits osteoclast differentiation by activating canonical and noncanonical cAMP/PKA pathways J. Bone Min. Res. 2016 31 65 75 10.1002/jbmr.2599
Weivoda, M. M. et al. Wnt signaling inhibits osteoclast differentiation by activating canonical and noncanonical cAMP/PKA pathways. J. Bone Min. Res. 31, 65–75 (2016).
291. Min SH Hypothalamic AMP-activated protein kinase as a whole-body energy sensor and regulator Endocrinol. Metab. (Seoul.) 2024 39 1 11 10.3803/EnM.2024.1922 38356211
Min, S. H. et al. Hypothalamic AMP-activated protein kinase as a whole-body energy sensor and regulator. Endocrinol. Metab. (Seoul.) 39, 1–11 (2024).38356211
292. Hardie DG Ross FA Hawley SA AMPK: a nutrient and energy sensor that maintains energy homeostasis Nat. Rev. Mol. Cell Biol. 2012 13 251 262 10.1038/nrm3311 22436748
Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).22436748
293. Yun B Prostaglandins from cytosolic phospholipase A2α/Cyclooxygenase-1 pathway and mitogen-activated protein kinases regulate gene expression in candida albicans-infected macrophages J. Biol. Chem. 2016 291 7070 7086 10.1074/jbc.M116.714873 26841868
Yun, B. et al. Prostaglandins from cytosolic phospholipase A2α/Cyclooxygenase-1 pathway and mitogen-activated protein kinases regulate gene expression in candida albicans-infected macrophages. J. Biol. Chem. 291, 7070–7086 (2016).26841868
294. Chen XL Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism J. Biol. Chem. 2003 278 703 711 10.1074/jbc.M203161200 12370194
Chen, X. L. et al. Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism. J. Biol. Chem. 278, 703–711 (2003).12370194
295. Kaneko Y Nimmerjahn F Ravetch JV Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation Science 2006 313 670 673 10.1126/science.1129594 16888140
Kaneko, Y., Nimmerjahn, F. & Ravetch, J. V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313, 670–673 (2006).16888140
296. Cogswell JP NF-kappa B regulates IL-1 beta transcription through a consensus NF-kappa B binding site and a nonconsensus CRE-like site J. Immunol. 1994 153 712 723 10.4049/jimmunol.153.2.712 8021507
Cogswell, J. P. et al. NF-kappa B regulates IL-1 beta transcription through a consensus NF-kappa B binding site and a nonconsensus CRE-like site. J. Immunol. 153, 712–723 (1994).8021507
297. Liu SF Malik AB NF-kappa B activation as a pathological mechanism of septic shock and inflammation Am. J. Physiol. Lung Cell Mol. Physiol. 2006 290 L622 l645 10.1152/ajplung.00477.2005 16531564
Liu, S. F. & Malik, A. B. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell Mol. Physiol. 290, L622–l645 (2006).16531564
298. Jung YJ IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis Faseb j. 2003 17 2115 2117 10.1096/fj.03-0329fje 12958148
Jung, Y. J. et al. IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. Faseb j. 17, 2115–2117 (2003).12958148
299. Burke JR BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice J. Biol. Chem. 2003 278 1450 1456 10.1074/jbc.M209677200 12403772
Burke, J. R. et al. BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. J. Biol. Chem. 278, 1450–1456 (2003).12403772
300. Josephson AM Systemic NF-κB-mediated inflammation promotes an aging phenotype in skeletal stem/progenitor cells Aging (Albany NY) 2021 13 13421 13429 10.18632/aging.203083 34035186
Josephson, A. M. et al. Systemic NF-κB-mediated inflammation promotes an aging phenotype in skeletal stem/progenitor cells. Aging (Albany NY) 13, 13421–13429 (2021).34035186
301. Cao QT Ishak M Shpilman I Hirota JA TNF-α and Poly(I:C) induction of A20 and activation of NF-κB signaling are independent of ABCF1 in human airway epithelial cells Sci. Rep. 2023 13 14745 10.1038/s41598-023-41990-w 37679460
Cao, Q. T., Ishak, M., Shpilman, I. & Hirota, J. A. TNF-α and Poly(I:C) induction of A20 and activation of NF-κB signaling are independent of ABCF1 in human airway epithelial cells. Sci. Rep. 13, 14745 (2023).37679460
302. Ebata, T. et al. Flightless I is a catabolic factor of chondrocytes that promotes hypertrophy and cartilage degeneration in osteoarthritis. iScience 24, 1–16 (2021).
303. Zhao D Anti-neuroinflammatory effects of fucoxanthin via inhibition of Akt/NF-κB and MAPKs/AP-1 pathways and activation of PKA/CREB pathway in lipopolysaccharide-activated BV-2 microglial cells Neurochem Res. 2017 42 667 677 10.1007/s11064-016-2123-6 27933547
Zhao, D. et al. Anti-neuroinflammatory effects of fucoxanthin via inhibition of Akt/NF-κB and MAPKs/AP-1 pathways and activation of PKA/CREB pathway in lipopolysaccharide-activated BV-2 microglial cells. Neurochem Res. 42, 667–677 (2017).27933547
304. Liang F Gardner DG Mechanical strain activates BNP gene transcription through a p38/NF-kappaB-dependent mechanism J. Clin. Invest 1999 104 1603 1612 10.1172/JCI7362 10587524
Liang, F. & Gardner, D. G. Mechanical strain activates BNP gene transcription through a p38/NF-kappaB-dependent mechanism. J. Clin. Invest 104, 1603–1612 (1999).10587524
305. Sica GL RELT, a new member of the tumor necrosis factor receptor superfamily, is selectively expressed in hematopoietic tissues and activates transcription factor NF-kappaB Blood 2001 97 2702 2707 10.1182/blood.V97.9.2702 11313261
Sica, G. L. et al. RELT, a new member of the tumor necrosis factor receptor superfamily, is selectively expressed in hematopoietic tissues and activates transcription factor NF-kappaB. Blood 97, 2702–2707 (2001).11313261
306. Guo C Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages Braz. J. Med. Biol. Res. 2016 49 e5826 10.1590/1414-431x20165826 27878229
Guo, C. et al. Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages. Braz. J. Med. Biol. Res. 49, e5826 (2016).27878229
307. Abdalqadir, N. & Adeli, K. GLP-1 and GLP-2 Orchestrate intestine integrity, gut microbiota, and immune system crosstalk. Microorganisms. 10, 2061 (2022).
308. Lam NT Kieffer TJ The multifaceted potential of glucagon-like peptide-1 as a therapeutic agent Minerva Endocrinol. 2002 27 79 93 11961501
Lam, N. T. & Kieffer, T. J. The multifaceted potential of glucagon-like peptide-1 as a therapeutic agent. Minerva Endocrinol. 27, 79–93 (2002).11961501
309. Wang L Feng L Zhang J Liraglutide exhibits anti-inflammatory activity through the activation of the PKA/CREB pathway J. Inflamm. (Lond.) 2019 16 21 10.1186/s12950-019-0225-z 31632200
Wang, L., Feng, L. & Zhang, J. Liraglutide exhibits anti-inflammatory activity through the activation of the PKA/CREB pathway. J. Inflamm. (Lond.) 16, 21 (2019).31632200
310. Masson AO Krawetz RJ Understanding cartilage protection in OA and injury: A spectrum of possibilities BMC Musculoskelet. Disord. 2020 21 432 10.1186/s12891-020-03363-6 32620156
Masson, A. O. & Krawetz, R. J. Understanding cartilage protection in OA and injury: A spectrum of possibilities. BMC Musculoskelet. Disord. 21, 432 (2020).32620156
311. Bennell KL Effect of intra-articular platelet-rich plasma vs placebo injection on pain and medial tibial cartilage volume in patients with knee osteoarthritis: The RESTORE Randomized Clinical Trial JAMA 2021 326 2021 2030 10.1001/jama.2021.19415 34812863
Bennell, K. L. et al. Effect of intra-articular platelet-rich plasma vs placebo injection on pain and medial tibial cartilage volume in patients with knee osteoarthritis: The RESTORE Randomized Clinical Trial. JAMA 326, 2021–2030 (2021).34812863
312. Fang Y Liraglutide alleviates hepatic steatosis by activating the TFEB-regulated autophagy-lysosomal pathway Front Cell Dev. Biol. 2020 8 602574 10.3389/fcell.2020.602574 33330497
Fang, Y. et al. Liraglutide alleviates hepatic steatosis by activating the TFEB-regulated autophagy-lysosomal pathway. Front Cell Dev. Biol. 8, 602574 (2020).33330497
313. Wu, M. Y. & Lu, J. H. Autophagy and macrophage functions: inflammatory response and phagocytosis. Cells 9, 70 (2019).
314. Perrotta C Cattaneo MG Molteni R De Palma C Autophagy in the regulation of tissue differentiation and homeostasis Front Cell Dev. Biol. 2020 8 602901 10.3389/fcell.2020.602901 33363161
Perrotta, C., Cattaneo, M. G., Molteni, R. & De Palma, C. Autophagy in the regulation of tissue differentiation and homeostasis. Front Cell Dev. Biol. 8, 602901 (2020).33363161
315. Arai T Analgesic effects and arthritic changes following intra-articular injection of diclofenac etalhyaluronate in a rat knee osteoarthritis model BMC Musculoskelet. Disord. 2022 23 960 10.1186/s12891-022-05937-y 36344944
Arai, T. et al. Analgesic effects and arthritic changes following intra-articular injection of diclofenac etalhyaluronate in a rat knee osteoarthritis model. BMC Musculoskelet. Disord. 23, 960 (2022).36344944
316. Yoh S Intra-articular injection of monoiodoacetate induces diverse hip osteoarthritis in rats, depending on its dose BMC Musculoskelet. Disord. 2022 23 494 10.1186/s12891-022-05454-y 35614438
Yoh, S. et al. Intra-articular injection of monoiodoacetate induces diverse hip osteoarthritis in rats, depending on its dose. BMC Musculoskelet. Disord. 23, 494 (2022).35614438
317. Takahashi I Matsuzaki T Kuroki H Hoso M Induction of osteoarthritis by injecting monosodium iodoacetate into the patellofemoral joint of an experimental rat model PLoS One 2018 13 e0196625 10.1371/journal.pone.0196625 29698461
Takahashi, I., Matsuzaki, T., Kuroki, H. & Hoso, M. Induction of osteoarthritis by injecting monosodium iodoacetate into the patellofemoral joint of an experimental rat model. PLoS One 13, e0196625 (2018).29698461
318. Wan S Sun H Glucagon-like peptide-1 modulates RAW264.7 macrophage polarization by interfering with the JNK/STAT3 signaling pathway Exp. Ther. Med. 2019 17 3573 3579 30988739
Wan, S. & Sun, H. Glucagon-like peptide-1 modulates RAW264.7 macrophage polarization by interfering with the JNK/STAT3 signaling pathway. Exp. Ther. Med. 17, 3573–3579 (2019).30988739
319. Hu Y Dong Z Liu K Unraveling the complexity of STAT3 in cancer: Molecular understanding and drug discovery J. Exp. Clin. Cancer Res. 2024 43 23 10.1186/s13046-024-02949-5 38245798
Hu, Y., Dong, Z. & Liu, K. Unraveling the complexity of STAT3 in cancer: Molecular understanding and drug discovery. J. Exp. Clin. Cancer Res. 43, 23 (2024).38245798
320. Xiong A Transcription factor STAT3 as a novel molecular target for cancer prevention Cancers (Basel) 2014 6 926 957 10.3390/cancers6020926 24743778
Xiong, A. et al. Transcription factor STAT3 as a novel molecular target for cancer prevention. Cancers (Basel) 6, 926–957 (2014).24743778
321. Liu S The regulatory relationship between transcription factor STAT3 and noncoding RNA Cell Mol. Biol. Lett. 2024 29 4 10.1186/s11658-023-00521-1 38172648
Liu, S. et al. The regulatory relationship between transcription factor STAT3 and noncoding RNA. Cell Mol. Biol. Lett. 29, 4 (2024).38172648
322. Wang N Exendin-4 induces bone marrow stromal cells migration through bone marrow-derived macrophages polarization via PKA-STAT3 signaling pathway Cell Physiol. Biochem 2017 44 1696 1714 10.1159/000485776 29216639
Wang, N. et al. Exendin-4 induces bone marrow stromal cells migration through bone marrow-derived macrophages polarization via PKA-STAT3 signaling pathway. Cell Physiol. Biochem 44, 1696–1714 (2017).29216639
323. Zhang X Wei-Tong-Xin exerts anti-inflammatory effects through TLR4-mediated macrophages M1/M2 polarization and affects GLP-1 secretion J. Pharm. Pharm. 2023 75 574 584 10.1093/jpp/rgad014
Zhang, X. et al. Wei-Tong-Xin exerts anti-inflammatory effects through TLR4-mediated macrophages M1/M2 polarization and affects GLP-1 secretion. J. Pharm. Pharm. 75, 574–584 (2023).
324. Yao Y Xu XH Jin L Macrophage polarization in physiological and pathological pregnancy Front Immunol. 2019 10 792 10.3389/fimmu.2019.00792 31037072
Yao, Y., Xu, X. H. & Jin, L. Macrophage polarization in physiological and pathological pregnancy. Front Immunol. 10, 792 (2019).31037072
325. Sica A Erreni M Allavena P Porta C Macrophage polarization in pathology Cell Mol. Life Sci. 2015 72 4111 4126 10.1007/s00018-015-1995-y 26210152
Sica, A., Erreni, M., Allavena, P. & Porta, C. Macrophage polarization in pathology. Cell Mol. Life Sci. 72, 4111–4126 (2015).26210152
326. Zhang H An orally active allosteric GLP-1 receptor agonist is neuroprotective in cellular and rodent models of stroke PLoS One 2016 11 e0148827 10.1371/journal.pone.0148827 26863436
Zhang, H. et al. An orally active allosteric GLP-1 receptor agonist is neuroprotective in cellular and rodent models of stroke. PLoS One 11, e0148827 (2016).26863436
327. Portha B Tourrel-Cuzin C Movassat J Activation of the GLP-1 receptor signalling pathway: A relevant strategy to repair a deficient beta-cell mass Exp. Diab Res. 2011 2011 376509 10.1155/2011/376509
Portha, B., Tourrel-Cuzin, C. & Movassat, J. Activation of the GLP-1 receptor signalling pathway: A relevant strategy to repair a deficient beta-cell mass. Exp. Diab Res. 2011, 376509 (2011).
328. Yusta B GLP-1R agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte GLP-1R Diabetes 2015 64 2537 2549 10.2337/db14-1577 25735732
Yusta, B. et al. GLP-1R agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte GLP-1R. Diabetes 64, 2537–2549 (2015).25735732
329. Akkiraju H Nohe A Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration J. Dev. Biol. 2015 3 177 192 10.3390/jdb3040177 27347486
Akkiraju, H. & Nohe, A. Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. J. Dev. Biol. 3, 177–192 (2015).27347486
330. Chen H Molecular mechanisms of chondrocyte proliferation and differentiation Front Cell Dev. Biol. 2021 9 664168 10.3389/fcell.2021.664168 34124045
Chen, H. et al. Molecular mechanisms of chondrocyte proliferation and differentiation. Front Cell Dev. Biol. 9, 664168 (2021).34124045
331. Li H Wang D Yuan Y Min J New insights on the MMP-13 regulatory network in the pathogenesis of early osteoarthritis Arthritis Res Ther. 2017 19 248 10.1186/s13075-017-1454-2 29126436
Li, H., Wang, D., Yuan, Y. & Min, J. New insights on the MMP-13 regulatory network in the pathogenesis of early osteoarthritis. Arthritis Res Ther. 19, 248 (2017).29126436
332. Tan, D. et al. Single‑cell sequencing, genetics, and epigenetics reveal mesenchymal stem cell senescence in osteoarthritis (Review). Int. J. Mol. Med. 53, 2 (2024).
333. Hu, Q. & Ecker, M. Overview of MMP-13 as a promising target for the treatment of osteoarthritis. Int. J. Mol. Sci. 22, 1742 (2021).
334. Jiang L ADAMTS5 in osteoarthritis: Biological functions, regulatory network, and potential targeting therapies Front Mol. Biosci. 2021 8 703110 10.3389/fmolb.2021.703110 34434966
Jiang, L. et al. ADAMTS5 in osteoarthritis: Biological functions, regulatory network, and potential targeting therapies. Front Mol. Biosci. 8, 703110 (2021).34434966
335. Zamora R Vodovotz Y Billiar TR Inducible nitric oxide synthase and inflammatory diseases Mol. Med. 2000 6 347 373 10.1007/BF03401781 10952018
Zamora, R., Vodovotz, Y. & Billiar, T. R. Inducible nitric oxide synthase and inflammatory diseases. Mol. Med. 6, 347–373 (2000).10952018
336. Cinelli MA Do HT Miley GP Silverman RB Inducible nitric oxide synthase: Regulation, structure, and inhibition Med Res Rev. 2020 40 158 189 10.1002/med.21599 31192483
Cinelli, M. A., Do, H. T., Miley, G. P. & Silverman, R. B. Inducible nitric oxide synthase: Regulation, structure, and inhibition. Med Res Rev. 40, 158–189 (2020).31192483
337. Liu L Progranulin inhibits LPS-induced macrophage M1 polarization via NF-кB and MAPK pathways BMC Immunol. 2020 21 32 10.1186/s12865-020-00355-y
Liu, L. et al. Progranulin inhibits LPS-induced macrophage M1 polarization via NF-кB and MAPK pathways. BMC Immunol. 21, 32 (2020).
338. Tak PP Firestein GS NF-kappaB: A key role in inflammatory diseases J. Clin. Invest 2001 107 7 11 10.1172/JCI11830 11134171
Tak, P. P. & Firestein, G. S. NF-kappaB: A key role in inflammatory diseases. J. Clin. Invest 107, 7–11 (2001).11134171
339. Li Q Verma IM NF-kappaB regulation in the immune system Nat. Rev. Immunol. 2002 2 725 734 10.1038/nri910 12360211
Li, Q. & Verma, I. M. NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).12360211
340. Anton SE Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling Cell 2022 185 1130 1142.e1111 10.1016/j.cell.2022.02.011 35294858
Anton, S. E. et al. Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling. Cell 185, 1130–1142.e1111 (2022).35294858
341. Park T N-Docosahexaenoylethanolamine ameliorates LPS-induced neuroinflammation via cAMP/PKA-dependent signaling J. Neuroinflammation 2016 13 284 10.1186/s12974-016-0751-z 27809877
Park, T. et al. N-Docosahexaenoylethanolamine ameliorates LPS-induced neuroinflammation via cAMP/PKA-dependent signaling. J. Neuroinflammation 13, 284 (2016).27809877
342. Vincenti MP Brinckerhoff CE Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors Arthritis Res. 2002 4 157 164 10.1186/ar401 12010565
Vincenti, M. P. & Brinckerhoff, C. E. Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res. 4, 157–164 (2002).12010565
343. Wang XP Quercetin suppresses apoptosis of chondrocytes induced by IL-1β via inactivation of p38 MAPK signaling pathway Exp. Ther. Med. 2021 21 468 10.3892/etm.2021.9899 33767763
Wang, X. P. et al. Quercetin suppresses apoptosis of chondrocytes induced by IL-1β via inactivation of p38 MAPK signaling pathway. Exp. Ther. Med. 21, 468 (2021).33767763
344. Gao, X. et al. Piceatannol suppresses inflammation and promotes apoptosis in rheumatoid arthritis‑fibroblast‑like synoviocytes by inhibiting the NF‑κB and MAPK signaling pathways. Mol. Med. Rep. 25, 294–304 (2022).
345. Ma X GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential Int. J. Biol. Sci. 2021 17 2050 2068 10.7150/ijbs.59965 34131405
Ma, X. et al. GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential. Int. J. Biol. Sci. 17, 2050–2068 (2021).34131405
346. Li S From hyperglycemia to intervertebral disc damage: Exploring diabetic-induced disc degeneration Front Immunol. 2024 15 1355503 10.3389/fimmu.2024.1355503 38444852
Li, S. et al. From hyperglycemia to intervertebral disc damage: Exploring diabetic-induced disc degeneration. Front Immunol. 15, 1355503 (2024).38444852
347. Tripolino C Insulin signaling in arthritis Front Immunol. 2021 12 672519 10.3389/fimmu.2021.672519 33995414
Tripolino, C. et al. Insulin signaling in arthritis. Front Immunol. 12, 672519 (2021).33995414
348. Meurot C Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis Sci. Rep. 2022 12 1567 10.1038/s41598-022-05323-7 35091584
Meurot, C. et al. Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis. Sci. Rep. 12, 1567 (2022).35091584
349. Wu, Q., Zhu, S., Liu, Y., Liao, C., Liang, Y. & Wu, G. Liraglutide suppresses TNF-α-induced degradation of extracellular matrix in human chondrocytes: a therapeutic implication in osteoarthritis. Inflamm. Res. (Switzerland, 2019).
350. Siddhanti S Thu0054 Nktr-358, a Novel Il-2 conjugate, stimulates high levels of regulatory T cells in patients with systemic lupus erythematosus Ann. Rheum. Dis. 2020 79 238.232 239 10.1136/annrheumdis-2020-eular.3165
Siddhanti, S. et al. Thu0054 Nktr-358, a Novel Il-2 conjugate, stimulates high levels of regulatory T cells in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 79, 238.232–239 (2020).
351. Oezer K The effect of GLP-1 receptor agonist lixisenatide on experimental diabetic retinopathy Acta Diabetol. 2023 60 1551 1565 10.1007/s00592-023-02135-7 37423944
Oezer, K. et al. The effect of GLP-1 receptor agonist lixisenatide on experimental diabetic retinopathy. Acta Diabetol. 60, 1551–1565 (2023).37423944
352. Bendotti G The anti-inflammatory and immunological properties of GLP-1 receptor agonists Pharm. Res. 2022 182 106320 10.1016/j.phrs.2022.106320
Bendotti, G. et al. The anti-inflammatory and immunological properties of GLP-1 receptor agonists. Pharm. Res. 182, 106320 (2022).
353. Du X The protective effects of lixisenatide against inflammatory response in human rheumatoid arthritis fibroblast-like synoviocytes Int Immunopharmacol. 2019 75 105732 10.1016/j.intimp.2019.105732 31336333
Du, X. et al. The protective effects of lixisenatide against inflammatory response in human rheumatoid arthritis fibroblast-like synoviocytes. Int Immunopharmacol. 75, 105732 (2019).31336333
354. Sellam J Berenbaum F The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis Nat. Rev. Rheumatol. 2010 6 625 635 10.1038/nrrheum.2010.159 20924410
Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).20924410
355. Xu J The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review Front Immunol. 2023 14 1222129 10.3389/fimmu.2023.1222129 37475866
Xu, J. et al. The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review. Front Immunol. 14, 1222129 (2023).37475866
356. Zhang Y Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats Nat. Med. 2016 22 1160 1169 10.1038/nm.4162 27571347
Zhang, Y. et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat. Med. 22, 1160–1169 (2016).27571347
357. Srivastava, R. K., Sapra, L. & Mishra, P. K. Osteometabolism: Metabolic alterations in bone pathologies. Cells 11, 14655 (2022).
358. Datta HK The cell biology of bone metabolism J. Clin. Pathol. 2008 61 577 587 10.1136/jcp.2007.048868 18441154
Datta, H. K. et al. The cell biology of bone metabolism. J. Clin. Pathol. 61, 577–587 (2008).18441154
359. Wang N Identification of a prolonged action molecular GLP-1R agonist for the treatment of femoral defects Biomater. Sci. 2020 8 1604 1614 10.1039/C9BM01426H 31967113
Wang, N. et al. Identification of a prolonged action molecular GLP-1R agonist for the treatment of femoral defects. Biomater. Sci. 8, 1604–1614 (2020).31967113
360. Kim, J. Y. et al. Exendin-4 increases bone mineral density in type 2 diabetic OLETF rats potentially through the down-regulation of SOST/sclerostin in osteocytes. Life Sci. 92, 8–15 (2013).
361. Koren N Exposure to omega-3 fatty acids at early age accelerate bone growth and improve bone quality J. Nutr. Biochem 2014 25 623 633 10.1016/j.jnutbio.2014.01.012 24746838
Koren, N. et al. Exposure to omega-3 fatty acids at early age accelerate bone growth and improve bone quality. J. Nutr. Biochem 25, 623–633 (2014).24746838
362. Yamada C The murine glucagon-like peptide-1 receptor is essential for control of bone resorption Endocrinology 2008 149 574 579 10.1210/en.2007-1292 18039776
Yamada, C. et al. The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 149, 574–579 (2008).18039776
363. Shen WR The Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 Inhibits Lipopolysaccharide-Induced Osteoclast Formation and Bone Resorption via Inhibition of TNF-alpha Expression in Macrophages J. Immunol. Res. 2018 2018 5783639 10.1155/2018/5783639 29725604
Shen, W. R. et al. The Glucagon-Like Peptide-1 Receptor Agonist Exendin-4 Inhibits Lipopolysaccharide-Induced Osteoclast Formation and Bone Resorption via Inhibition of TNF-alpha Expression in Macrophages. J. Immunol. Res. 2018, 5783639 (2018).29725604
364. Ishida M DPP-4 inhibitor impedes lipopolysaccharide-induced osteoclast formation and bone resorption in vivo Biomed. Pharmacother. 2019 109 242 253 10.1016/j.biopha.2018.10.052 30396082
Ishida, M. et al. DPP-4 inhibitor impedes lipopolysaccharide-induced osteoclast formation and bone resorption in vivo. Biomed. Pharmacother. 109, 242–253 (2019).30396082
365. Nuche-Berenguer B GLP-1 and exendin-4 can reverse hyperlipidic-related osteopenia J. Endocrinol. 2011 209 203 210 10.1530/JOE-11-0015 21372151
Nuche-Berenguer, B. et al. GLP-1 and exendin-4 can reverse hyperlipidic-related osteopenia. J. Endocrinol. 209, 203–210 (2011).21372151
366. Li G Frailty and Risk of Fractures in Patients With Type 2 Diabetes Diab Care 2019 42 507 513 10.2337/dc18-1965
Li, G. et al. Frailty and Risk of Fractures in Patients With Type 2 Diabetes. Diab Care 42, 507–513 (2019).
367. Yu J Liraglutide Inhibits Osteoclastogenesis and Improves Bone Loss by Downregulating Trem2 in Female Type 1 Diabetic Mice: Findings From Transcriptomics Front Endocrinol. (Lausanne) 2021 12 763646 10.3389/fendo.2021.763646 34975749
Yu, J. et al. Liraglutide Inhibits Osteoclastogenesis and Improves Bone Loss by Downregulating Trem2 in Female Type 1 Diabetic Mice: Findings From Transcriptomics. Front Endocrinol. (Lausanne) 12, 763646 (2021).34975749
368. Tsukiyama K Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion Mol. Endocrinol. 2006 20 1644 1651 10.1210/me.2005-0187 16469773
Tsukiyama, K. et al. Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion. Mol. Endocrinol. 20, 1644–1651 (2006).16469773
369. Crespel, A., De Boisvilliers, F., Gros, L., Kervran, A. Effects of glucagon and glucagon-like peptide-1-(7-36) amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line. Endocrinology 137, 3674–3680 (1996).
370. Lamari, Y. Expression of glucagon-like peptide 1 receptor in a murine C cell line: regulation of calcitonin gene by glucagon-like peptide 1. FEBS Lett. 393, 248–252 (1996).
371. Meng J Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through beta-Catenin Stem Cell Rep. 2016 6 579 591 10.1016/j.stemcr.2016.02.002
Meng, J. et al. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through beta-Catenin. Stem Cell Rep. 6, 579–591 (2016).
372. Berenbaum, F., Bougault, C. & Attali, C. Treatment of osteoarthritis with incretin hormones or analogues thereof. US 09592272 (2017).
373. Pacheco-Pantoja EL c-Fos induction by gut hormones and extracellular ATP in osteoblastic-like cell lines Purinergic Signal. 2016 12 647 651 10.1007/s11302-016-9526-3 27439698
Pacheco-Pantoja, E. L. et al. c-Fos induction by gut hormones and extracellular ATP in osteoblastic-like cell lines. Purinergic Signal. 12, 647–651 (2016).27439698
374. Ma X Exendin-4, a glucagon-like peptide-1 receptor agonist, prevents osteopenia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats J. Bone Min. Res 2013 28 1641 1652 10.1002/jbmr.1898
Ma, X. et al. Exendin-4, a glucagon-like peptide-1 receptor agonist, prevents osteopenia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats. J. Bone Min. Res. 28, 1641–1652 (2013).
375. Wu X Li S Xue P Li Y Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving beta-catenin Exp. Cell Res 2017 360 281 291 10.1016/j.yexcr.2017.09.018 28919123
Wu, X., Li, S., Xue, P. & Li, Y. Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving beta-catenin. Exp. Cell Res. 360, 281–291 (2017).28919123
376. Kamiya M Mizoguchi F Yasuda S Amelioration of inflammatory myopathies by glucagon-like peptide-1 receptor agonist via suppressing muscle fibre necroptosis J. Cachexia Sarcopenia Muscle 2022 13 2118 2131 10.1002/jcsm.13025 35775116
Kamiya, M., Mizoguchi, F. & Yasuda, S. Amelioration of inflammatory myopathies by glucagon-like peptide-1 receptor agonist via suppressing muscle fibre necroptosis. J. Cachexia Sarcopenia Muscle 13, 2118–2131 (2022).35775116
377. Deng F Dulaglutide protects mice against diabetic sarcopenia-mediated muscle injury by inhibiting inflammation and regulating the differentiation of myoblasts Int. J. Endocrinol. 2023 2023 9926462 10.1155/2023/9926462 37584041
Deng, F. et al. Dulaglutide protects mice against diabetic sarcopenia-mediated muscle injury by inhibiting inflammation and regulating the differentiation of myoblasts. Int. J. Endocrinol. 2023, 9926462 (2023).37584041
378. Nguyen TTN Choi H Jun HS Preventive effects of dulaglutide on disuse muscle atrophy through inhibition of inflammation and apoptosis by induction of Hsp72 expression Front Pharm. 2020 11 90 10.3389/fphar.2020.00090
Nguyen, T. T. N., Choi, H. & Jun, H. S. Preventive effects of dulaglutide on disuse muscle atrophy through inhibition of inflammation and apoptosis by induction of Hsp72 expression. Front Pharm. 11, 90 (2020).
379. Hong Y Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy J. Cachexia Sarcopenia Muscle 2019 10 903 918 10.1002/jcsm.12434 31020810
Hong, Y. et al. Amelioration of muscle wasting by glucagon-like peptide-1 receptor agonist in muscle atrophy. J. Cachexia Sarcopenia Muscle 10, 903–918 (2019).31020810
380. Rajagopal S Glucagon-like peptide-1 receptor agonists in the treatment of idiopathic inflammatory myopathy: from mechanisms of action to clinical applications Cureus 2023 15 e51352 38292961
Rajagopal, S. et al. Glucagon-like peptide-1 receptor agonists in the treatment of idiopathic inflammatory myopathy: from mechanisms of action to clinical applications. Cureus 15, e51352 (2023).38292961
381. Hanaoka BY Peterson CA Horbinski C Crofford LJ Implications of glucocorticoid therapy in idiopathic inflammatory myopathies Nat. Rev. Rheumatol. 2012 8 448 457 10.1038/nrrheum.2012.85 22688888
Hanaoka, B. Y., Peterson, C. A., Horbinski, C. & Crofford, L. J. Implications of glucocorticoid therapy in idiopathic inflammatory myopathies. Nat. Rev. Rheumatol. 8, 448–457 (2012).22688888
382. Kamiya M Muscle fiber necroptosis in pathophysiology of idiopathic inflammatory myopathies and its potential as target of novel treatment strategy Front Immunol. 2023 14 1191815 10.3389/fimmu.2023.1191815 37483632
Kamiya, M. et al. Muscle fiber necroptosis in pathophysiology of idiopathic inflammatory myopathies and its potential as target of novel treatment strategy. Front Immunol. 14, 1191815 (2023).37483632
383. Cui Y The role of AMPK in macrophage metabolism, function and polarisation J. Transl. Med. 2023 21 892 10.1186/s12967-023-04772-6 38066566
Cui, Y. et al. The role of AMPK in macrophage metabolism, function and polarisation. J. Transl. Med. 21, 892 (2023).38066566
384. Yi D AMPK signaling in energy control, cartilage biology, and osteoarthritis Front Cell Dev. Biol. 2021 9 696602 10.3389/fcell.2021.696602 34239878
Yi, D. et al. AMPK signaling in energy control, cartilage biology, and osteoarthritis. Front Cell Dev. Biol. 9, 696602 (2021).34239878
385. Zhao Y ROS signaling under metabolic stress: Cross-talk between AMPK and AKT pathway Mol. Cancer 2017 16 79 10.1186/s12943-017-0648-1 28407774
Zhao, Y. et al. ROS signaling under metabolic stress: Cross-talk between AMPK and AKT pathway. Mol. Cancer 16, 79 (2017).28407774
386. Li J Phosphoglycerate mutase 5 initiates inflammation in acute kidney injury by triggering mitochondrial DNA release by dephosphorylating the pro-apoptotic protein Bax Kidney Int 2023 103 115 133 10.1016/j.kint.2022.08.022 36089186
Li, J. et al. Phosphoglycerate mutase 5 initiates inflammation in acute kidney injury by triggering mitochondrial DNA release by dephosphorylating the pro-apoptotic protein Bax. Kidney Int 103, 115–133 (2023).36089186
387. Yan S ZBP1 promotes hepatocyte pyroptosis in acute liver injury by regulating the PGAM5/ROS pathway Ann. Hepatol. 2024 29 101475 10.1016/j.aohep.2024.101475 38331384
Yan, S. et al. ZBP1 promotes hepatocyte pyroptosis in acute liver injury by regulating the PGAM5/ROS pathway. Ann. Hepatol. 29, 101475 (2024).38331384
388. Holliday A Blannin A Appetite, food intake and gut hormone responses to intense aerobic exercise of different duration J. Endocrinol. 2017 235 193 205 10.1530/JOE-16-0570 28870887
Holliday, A. & Blannin, A. Appetite, food intake and gut hormone responses to intense aerobic exercise of different duration. J. Endocrinol. 235, 193–205 (2017).28870887
389. Wu L GLP-1 regulates exercise endurance and skeletal muscle remodeling via GLP-1R/AMPK pathway Biochim. Biophys. Acta Mol. Cell Res 2022 1869 119300 10.1016/j.bbamcr.2022.119300 35636559
Wu, L. et al. GLP-1 regulates exercise endurance and skeletal muscle remodeling via GLP-1R/AMPK pathway. Biochim. Biophys. Acta Mol. Cell Res. 1869, 119300 (2022).35636559
390. Bodnaruc AM Prud’homme D Blanchet R Giroux I Nutritional modulation of endogenous glucagon-like peptide-1 secretion: A review Nutr. Metab. (Lond.) 2016 13 92 10.1186/s12986-016-0153-3 27990172
Bodnaruc, A. M., Prud’homme, D., Blanchet, R. & Giroux, I. Nutritional modulation of endogenous glucagon-like peptide-1 secretion: A review. Nutr. Metab. (Lond.) 13, 92 (2016).27990172
391. Ard J Fitch A Fruh S Herman L Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists Adv. Ther. 2021 38 2821 2839 10.1007/s12325-021-01710-0 33977495
Ard, J., Fitch, A., Fruh, S. & Herman, L. Weight loss and maintenance related to the mechanism of action of glucagon-like peptide 1 receptor agonists. Adv. Ther. 38, 2821–2839 (2021).33977495
392. Kanoski SE Hayes MR Skibicka KP GLP-1 and weight loss: unraveling the diverse neural circuitry Am. J. Physiol. -Regulatory, Integr. Comp. Physiol. 2016 310 R885 R895 10.1152/ajpregu.00520.2015
Kanoski, S. E., Hayes, M. R. & Skibicka, K. P. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am. J. Physiol. -Regulatory, Integr. Comp. Physiol. 310, R885–R895 (2016).
393. Greff D Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials Reprod. Biol. Endocrinol. 2023 21 10 10.1186/s12958-023-01055-z 36703143
Greff, D. et al. Inositol is an effective and safe treatment in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Reprod. Biol. Endocrinol. 21, 10 (2023).36703143
394. Kosinska MK Articular Joint Lubricants during Osteoarthritis and Rheumatoid Arthritis Display Altered Levels and Molecular Species PLoS One 2015 10 e0125192 10.1371/journal.pone.0125192 25933137
Kosinska, M. K. et al. Articular Joint Lubricants during Osteoarthritis and Rheumatoid Arthritis Display Altered Levels and Molecular Species. PLoS One 10, e0125192 (2015).25933137
395. Berenbaum, F. et al. Protective effects of intra-articular formulated liraglutide in osteoarthritis: Preclinical studies. Osteoarthritis Cartilage. 28, S405–S406 (2020).
396. Li H Chronic treatment of exendin-4 affects cell proliferation and neuroblast differentiation in the adult mouse hippocampal dentate gyrus Neurosci. Lett. 2010 486 38 42 10.1016/j.neulet.2010.09.040 20854877
Li, H. et al. Chronic treatment of exendin-4 affects cell proliferation and neuroblast differentiation in the adult mouse hippocampal dentate gyrus. Neurosci. Lett. 486, 38–42 (2010).20854877
397. Bertilsson G Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease J. Neurosci. Res. 2008 86 326 338 10.1002/jnr.21483 17803225
Bertilsson, G. et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J. Neurosci. Res. 86, 326–338 (2008).17803225
398. Sharma MK Jalewa J Hölscher C Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress J. Neurochem 2014 128 459 471 10.1111/jnc.12469 24112036
Sharma, M. K., Jalewa, J. & Hölscher, C. Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress. J. Neurochem 128, 459–471 (2014).24112036
399. Perry T Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4 J. Pharm. Exp. Ther. 2002 302 881 888 10.1124/jpet.102.037481
Perry, T. et al. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J. Pharm. Exp. Ther. 302, 881–888 (2002).
400. Jolivalt CG GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice Diab Obes. Metab. 2011 13 990 1000 10.1111/j.1463-1326.2011.01431.x
Jolivalt, C. G. et al. GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice. Diab Obes. Metab. 13, 990–1000 (2011).
401. Liu W Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease Neuroscience 2015 303 42 50 10.1016/j.neuroscience.2015.06.054 26141845
Liu, W. et al. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience 303, 42–50 (2015).26141845
402. Hunter K Hölscher C Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis BMC Neurosci. 2012 13 33 10.1186/1471-2202-13-33 22443187
Hunter, K. & Hölscher, C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 13, 33 (2012).22443187
403. Cai HY Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer’s disease Biochem Biophys. Res Commun. 2018 495 1034 1040 10.1016/j.bbrc.2017.11.114 29175324
Cai, H. Y. et al. Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer’s disease. Biochem Biophys. Res Commun. 495, 1034–1040 (2018).29175324
404. Beard E Astrocytes as key regulators of brain energy metabolism: New therapeutic perspectives Front Physiol. 2021 12 825816 10.3389/fphys.2021.825816 35087428
Beard, E. et al. Astrocytes as key regulators of brain energy metabolism: New therapeutic perspectives. Front Physiol. 12, 825816 (2021).35087428
405. Reiner DJ Astrocytes regulate GLP-1 receptor-mediated effects on energy balance J. Neurosci. 2016 36 3531 3540 10.1523/JNEUROSCI.3579-15.2016 27013681
Reiner, D. J. et al. Astrocytes regulate GLP-1 receptor-mediated effects on energy balance. J. Neurosci. 36, 3531–3540 (2016).27013681
406. Timper K GLP-1 receptor signaling in astrocytes regulates fatty acid oxidation, mitochondrial integrity, and function Cell Metab. 2020 31 1189 1205.e1113 10.1016/j.cmet.2020.05.001 32433922
Timper, K. et al. GLP-1 receptor signaling in astrocytes regulates fatty acid oxidation, mitochondrial integrity, and function. Cell Metab. 31, 1189–1205.e1113 (2020).32433922
407. González-García I Gruber T García-Cáceres C Insulin action on astrocytes: From energy homeostasis to behaviour J. Neuroendocrinol. 2021 33 e12953 10.1111/jne.12953 33724579
González-García, I., Gruber, T. & García-Cáceres, C. Insulin action on astrocytes: From energy homeostasis to behaviour. J. Neuroendocrinol. 33, e12953 (2021).33724579
408. Camandola S Astrocytes, emerging stars of energy homeostasis Cell Stress 2018 2 246 252 10.15698/cst2018.10.157 30417169
Camandola, S. Astrocytes, emerging stars of energy homeostasis. Cell Stress 2, 246–252 (2018).30417169
409. Lin MH The GLP-1 receptor agonist exenatide ameliorates neuroinflammation, locomotor activity, and anxiety-like behavior in mice with diet-induced obesity through the modulation of microglial M2 polarization and downregulation of SR-A4 Int Immunopharmacol. 2023 115 109653 10.1016/j.intimp.2022.109653 36587502
Lin, M. H. et al. The GLP-1 receptor agonist exenatide ameliorates neuroinflammation, locomotor activity, and anxiety-like behavior in mice with diet-induced obesity through the modulation of microglial M2 polarization and downregulation of SR-A4. Int Immunopharmacol. 115, 109653 (2023).36587502
410. Sango K Glucagon-like peptide-1 receptor agonists as potential myelination-inducible and anti-demyelinating remedies Front Cell Dev. Biol. 2022 10 950623 10.3389/fcell.2022.950623 35874814
Sango, K. et al. Glucagon-like peptide-1 receptor agonists as potential myelination-inducible and anti-demyelinating remedies. Front Cell Dev. Biol. 10, 950623 (2022).35874814
411. Cui SS Exendin-4 attenuates pain-induced cognitive impairment by alleviating hippocampal neuroinflammation in a rat model of spinal nerve ligation Neural Regen. Res. 2020 15 1333 1339 10.4103/1673-5374.272620 31960821
Cui, S. S. et al. Exendin-4 attenuates pain-induced cognitive impairment by alleviating hippocampal neuroinflammation in a rat model of spinal nerve ligation. Neural Regen. Res. 15, 1333–1339 (2020).31960821
412. Courties A Clearing method for 3-dimensional immunofluorescence of osteoarthritic subchondral human bone reveals peripheral cholinergic nerves Sci. Rep. 2020 10 8852 10.1038/s41598-020-65873-6 32483280
Courties, A. et al. Clearing method for 3-dimensional immunofluorescence of osteoarthritic subchondral human bone reveals peripheral cholinergic nerves. Sci. Rep. 10, 8852 (2020).32483280
413. Mehdi SF Glucagon-like peptide-1: A multi-faceted anti-inflammatory agent Front Immunol. 2023 14 1148209 10.3389/fimmu.2023.1148209 37266425
Mehdi, S. F. et al. Glucagon-like peptide-1: A multi-faceted anti-inflammatory agent. Front Immunol. 14, 1148209 (2023).37266425
414. Mehan S Potential roles of glucagon-like peptide-1 and its analogues in dementia targeting impaired insulin secretion and neurodegeneration Degener. Neurol. Neuromuscul. Dis. 2022 12 31 59 35300067
Mehan, S. et al. Potential roles of glucagon-like peptide-1 and its analogues in dementia targeting impaired insulin secretion and neurodegeneration. Degener. Neurol. Neuromuscul. Dis. 12, 31–59 (2022).35300067
415. Wang JY GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach Front Endocrinol. (Lausanne) 2023 14 1085799 10.3389/fendo.2023.1085799 36843578
Wang, J. Y. et al. GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach. Front Endocrinol. (Lausanne) 14, 1085799 (2023).36843578
416. Iepsen EW Torekov SS Holst JJ Therapies for inter-relating diabetes and obesity - GLP-1 and obesity Expert Opin. Pharmacother. 2014 15 2487 2500 10.1517/14656566.2014.965678 25260877
Iepsen, E. W., Torekov, S. S. & Holst, J. J. Therapies for inter-relating diabetes and obesity - GLP-1 and obesity. Expert Opin. Pharmacother. 15, 2487–2500 (2014).25260877
417. Eliaschewitz FG Canani LH Advances in GLP-1 treatment: Focus on oral semaglutide Diabetol. Metab. Syndr. 2021 13 99 10.1186/s13098-021-00713-9 34526121
Eliaschewitz, F. G. & Canani, L. H. Advances in GLP-1 treatment: Focus on oral semaglutide. Diabetol. Metab. Syndr. 13, 99 (2021).34526121
418. Krieger JP Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia Diabetes 2016 65 34 43 10.2337/db15-0973 26470787
Krieger, J. P. et al. Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia. Diabetes 65, 34–43 (2016).26470787
419. Hayes MR The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1 Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011 301 R1479 1485 10.1152/ajpregu.00356.2011 21849636
Hayes, M. R. et al. The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1479–1485 (2011).21849636
420. Krieger JP Langhans W Lee SJ Vagal mediation of GLP-1’s effects on food intake and glycemia Physiol. Behav. 2015 152 372 380 10.1016/j.physbeh.2015.06.001 26048300
Krieger, J. P., Langhans, W. & Lee, S. J. Vagal mediation of GLP-1’s effects on food intake and glycemia. Physiol. Behav. 152, 372–380 (2015).26048300
421. Skibicka KP The central GLP-1: implications for food and drug reward Front Neurosci. 2013 7 181 10.3389/fnins.2013.00181 24133407
Skibicka, K. P. The central GLP-1: implications for food and drug reward. Front Neurosci. 7, 181 (2013).24133407
422. Farr OM Longer-term liraglutide administration at the highest dose approved for obesity increases reward-related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti-obesity therapies Diab Obes. Metab. 2019 21 2459 2464 10.1111/dom.13827
Farr, O. M. et al. Longer-term liraglutide administration at the highest dose approved for obesity increases reward-related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti-obesity therapies. Diab Obes. Metab. 21, 2459–2464 (2019).
423. Wong CK Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation Cell Metab. 2024 36 130 143.e135 10.1016/j.cmet.2023.11.009 38113888
Wong, C. K. et al. Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation. Cell Metab. 36, 130–143.e135 (2024).38113888
424. Armstrong RA The pathogenesis of Alzheimer’s disease: a reevaluation of the “amyloid cascade hypothesis” Int J. Alzheimers Dis. 2011 2011 630865 10.4061/2011/630865 21331369
Armstrong, R. A. The pathogenesis of Alzheimer’s disease: a reevaluation of the “amyloid cascade hypothesis”. Int J. Alzheimers Dis. 2011, 630865 (2011).21331369
425. Egecioglu E Engel JA Jerlhag E The glucagon-like peptide 1 analogue Exendin-4 attenuates the nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice PLoS One 2013 8 e77284 10.1371/journal.pone.0077284 24204788
Egecioglu, E., Engel, J. A. & Jerlhag, E. The glucagon-like peptide 1 analogue Exendin-4 attenuates the nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice. PLoS One 8, e77284 (2013).24204788
426. Hölscher C The role of GLP-1 in neuronal activity and neurodegeneration Vitam. Horm. 2010 84 331 354 10.1016/B978-0-12-381517-0.00013-8 21094907
Hölscher, C. The role of GLP-1 in neuronal activity and neurodegeneration. Vitam. Horm. 84, 331–354 (2010).21094907
427. Li Y GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism Proc. Natl Acad. Sci. USA 2009 106 1285 1290 10.1073/pnas.0806720106 19164583
Li, Y. et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc. Natl Acad. Sci. USA 106, 1285–1290 (2009).19164583
428. Wang XH Val8-glucagon-like peptide-1 protects against Aβ1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats Neuroscience 2010 170 1239 1248 10.1016/j.neuroscience.2010.08.028 20727946
Wang, X. H. et al. Val8-glucagon-like peptide-1 protects against Aβ1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats. Neuroscience 170, 1239–1248 (2010).20727946
429. Perry T Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron J. Neurosci. Res 2003 72 603 612 10.1002/jnr.10611 12749025
Perry, T. et al. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J. Neurosci. Res 72, 603–612 (2003).12749025
430. Alamed, J. et al. The Effects of NLY01, a novel glucagon-like peptide-1 receptor agonist, on cuprizone-induced demyelination and remyelination: challenges and future perspectives. Neurotherapeutics 20, 1229–1240 (United States, 2023).
431. Nowell J Blunt E Gupta D Edison P Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease Ageing Res. Rev. 2023 89 101979 10.1016/j.arr.2023.101979 37328112
Nowell, J., Blunt, E., Gupta, D. & Edison, P. Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease. Ageing Res. Rev. 89, 101979 (2023).37328112
432. Meissner WG Trial of lixisenatide in early Parkinson’s disease N. Engl. J. Med. 2024 390 1176 1185 10.1056/NEJMoa2312323 38598572
Meissner, W. G. et al. Trial of lixisenatide in early Parkinson’s disease. N. Engl. J. Med. 390, 1176–1185 (2024).38598572
433. Aranäs C Semaglutide reduces alcohol intake and relapse-like drinking in male and female rats EBioMedicine 2023 93 104642 10.1016/j.ebiom.2023.104642 37295046
Aranäs, C. et al. Semaglutide reduces alcohol intake and relapse-like drinking in male and female rats. EBioMedicine 93, 104642 (2023).37295046
434. Järvinen A Laine MK Tikkanen R Castrén ML Beneficial effects of GLP-1 agonist in a male with compulsive food-related behavior associated with autism Front Psychiatry 2019 10 97 10.3389/fpsyt.2019.00097 30881319
Järvinen, A., Laine, M. K., Tikkanen, R. & Castrén, M. L. Beneficial effects of GLP-1 agonist in a male with compulsive food-related behavior associated with autism. Front Psychiatry 10, 97 (2019).30881319
435. Hanssen R Liraglutide restores impaired associative learning in individuals with obesity Nat. Metab. 2023 5 1352 1363 10.1038/s42255-023-00859-y 37592007
Hanssen, R. et al. Liraglutide restores impaired associative learning in individuals with obesity. Nat. Metab. 5, 1352–1363 (2023).37592007
436. Association learning is impaired in insulin resistance and restored by liraglutide. Nat Metab. 5, 1262-1263, (2023).
437. Walkowski, B., Kleibert, M., Majka, M. & Wojciechowska, M. Insight into the role of the PI3K/Akt pathway in ischemic injury and post-infarct left ventricular remodeling in normal and diabetic heart. Cells 11, 1553 (2022).
438. Fernandez Rico C Therapeutic peptides to treat myocardial ischemia-reperfusion injury Front Cardiovasc Med. 2022 9 792885 10.3389/fcvm.2022.792885 35252383
Fernandez Rico, C. et al. Therapeutic peptides to treat myocardial ischemia-reperfusion injury. Front Cardiovasc Med. 9, 792885 (2022).35252383
439. Vergès B Protection against stroke with glucagon-like peptide-1 receptor agonists: A comprehensive review of potential mechanisms Cardiovasc Diabetol. 2022 21 242 10.1186/s12933-022-01686-3 36380358
Vergès, B. et al. Protection against stroke with glucagon-like peptide-1 receptor agonists: A comprehensive review of potential mechanisms. Cardiovasc Diabetol. 21, 242 (2022).36380358
440. Helmstädter J Endothelial GLP-1 (glucagon-like peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension Arterioscler Thromb. Vasc. Biol. 2020 40 145 158 10.1161/atv.0000615456.97862.30 31747801
Helmstädter, J. et al. Endothelial GLP-1 (glucagon-like peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension. Arterioscler Thromb. Vasc. Biol. 40, 145–158 (2020).31747801
441. Cai Z Amelioration of endothelial dysfunction in diabetes: Role of Takeda G protein-coupled receptor 5 Front Pharm. 2021 12 637051 10.3389/fphar.2021.637051
Cai, Z. et al. Amelioration of endothelial dysfunction in diabetes: Role of Takeda G protein-coupled receptor 5. Front Pharm. 12, 637051 (2021).
442. Heimbürger SM Glucose-dependent insulinotropic polypeptide (GIP) and cardiovascular disease Peptides 2020 125 170174 10.1016/j.peptides.2019.170174 31689454
Heimbürger, S. M. et al. Glucose-dependent insulinotropic polypeptide (GIP) and cardiovascular disease. Peptides 125, 170174 (2020).31689454
443. Liu L Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism Hypertension 2012 60 833 841 10.1161/HYPERTENSIONAHA.112.195115 22868389
Liu, L. et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension 60, 833–841 (2012).22868389
444. Wang D Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism Diabetes 2013 62 1697 1708 10.2337/db12-1025 23364453
Wang, D. et al. Glucagon-like peptide-1 protects against cardiac microvascular injury in diabetes via a cAMP/PKA/Rho-dependent mechanism. Diabetes 62, 1697–1708 (2013).23364453
445. Noyan-Ashraf MH GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice Diabetes 2009 58 975 983 10.2337/db08-1193 19151200
Noyan-Ashraf, M. H. et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes 58, 975–983 (2009).19151200
446. Marso SP Liraglutide and cardiovascular outcomes in type 2 diabetes N. Engl. J. Med. 2016 375 311 322 10.1056/NEJMoa1603827 27295427
Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016).27295427
447. Buse JB Serum 1,5-anhydroglucitol (GlycoMark): a short-term glycemic marker Diab Technol. Ther. 2003 5 355 363 10.1089/152091503765691839
Buse, J. B. et al. Serum 1,5-anhydroglucitol (GlycoMark): a short-term glycemic marker. Diab Technol. Ther. 5, 355–363 (2003).
448. Marso SP Holst AG Vilsbøll T Semaglutide and cardiovascular outcomes in patients with type 2 diabetes N. Engl. J. Med. 2017 376 891 892 28249135
Marso, S. P., Holst, A. G. & Vilsbøll, T. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 376, 891–892 (2017).28249135
449. Ceriello A Evidence that hyperglycemia after recovery from hypoglycemia worsens endothelial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type 1 diabetes Diabetes 2012 61 2993 2997 10.2337/db12-0224 22891214
Ceriello, A. et al. Evidence that hyperglycemia after recovery from hypoglycemia worsens endothelial function and increases oxidative stress and inflammation in healthy control subjects and subjects with type 1 diabetes. Diabetes 61, 2993–2997 (2012).22891214
450. Monami M Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials Diab Obes. Metab. 2014 16 38 47 10.1111/dom.12175
Monami, M. et al. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diab Obes. Metab. 16, 38–47 (2014).
451. Vrieze A Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome Gastroenterology 2012 143 913 916.e917 10.1053/j.gastro.2012.06.031 22728514
Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916.e917 (2012).22728514
452. Kelly AS Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial Cardiovasc Diabetol. 2012 11 64 10.1186/1475-2840-11-64 22681705
Kelly, A. S. et al. Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial. Cardiovasc Diabetol. 11, 64 (2012).22681705
453. Nauck MA Quast DR Wefers J Meier JJ GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art Mol. Metab. 2021 46 101102 10.1016/j.molmet.2020.101102 33068776
Nauck, M. A., Quast, D. R., Wefers, J. & Meier, J. J. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol. Metab. 46, 101102 (2021).33068776
454. Jiménez N Tannin degradation by a novel tannase enzyme present in some Lactobacillus plantarum strains Appl. Environ. Microbiol 2014 80 2991 2997 10.1128/AEM.00324-14 24610854
Jiménez, N. et al. Tannin degradation by a novel tannase enzyme present in some Lactobacillus plantarum strains. Appl. Environ. Microbiol 80, 2991–2997 (2014).24610854
455. Moore PA Cuddy MA Cooke MR Sokolowski CJ Periodontal ligament and intraosseous anesthetic injection techniques: Alternatives to mandibular nerve blocks J. Am. Dent. Assoc. 2011 142 13s 18s 10.14219/jada.archive.2011.0342 21881057
Moore, P. A., Cuddy, M. A., Cooke, M. R. & Sokolowski, C. J. Periodontal ligament and intraosseous anesthetic injection techniques: Alternatives to mandibular nerve blocks. J. Am. Dent. Assoc. 142, 13s–18s (2011).21881057
456. Ali A Yalçın R Ünlüer-Gümüştaş A Cranial MR characteristics of Cerebral Palsy cases and correlation of findings with clinical results Turk. J. Pediatr. 2019 61 525 537 10.24953/turkjped.2019.04.009 31990470
Ali, A., Yalçın, R. & Ünlüer-Gümüştaş, A. Cranial MR characteristics of Cerebral Palsy cases and correlation of findings with clinical results. Turk. J. Pediatr. 61, 525–537 (2019).31990470
457. Ridker PM Thuren T Zalewski A Libby P Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) Am. Heart J. 2011 162 597 605 10.1016/j.ahj.2011.06.012 21982649
Ridker, P. M., Thuren, T., Zalewski, A. & Libby, P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am. Heart J. 162, 597–605 (2011).21982649
458. Everett, B. M. et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am. Heart J. 166, 199–207.e115 (2013).
459. Libby P Ridker PM Hansson GK Inflammation in atherosclerosis: from pathophysiology to practice J. Am. Coll. Cardiol. 2009 54 2129 2138 10.1016/j.jacc.2009.09.009 19942084
Libby, P., Ridker, P. M. & Hansson, G. K. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54, 2129–2138 (2009).19942084
460. Ross R Atherosclerosis–an inflammatory disease N. Engl. J. Med. 1999 340 115 126 10.1056/NEJM199901143400207 9887164
Ross, R. Atherosclerosis–an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).9887164
461. Nikolaidis LA Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines J. Pharm. Exp. Ther. 2005 312 303 308 10.1124/jpet.104.073890
Nikolaidis, L. A. et al. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J. Pharm. Exp. Ther. 312, 303–308 (2005).
462. Younce CW Burmeister MA Ayala JE Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a Am. J. Physiol. Cell Physiol. 2013 304 C508 518 10.1152/ajpcell.00248.2012 23302777
Younce, C. W., Burmeister, M. A. & Ayala, J. E. Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am. J. Physiol. Cell Physiol. 304, C508–518 (2013).23302777
463. Esser N Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes Diab Res Clin. Pr. 2014 105 141 150 10.1016/j.diabres.2014.04.006
Esser, N. et al. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diab Res Clin. Pr. 105, 141–150 (2014).
464. Paton JF The carotid body as a therapeutic target for the treatment of sympathetically mediated diseases Hypertension 2013 61 5 13 10.1161/HYPERTENSIONAHA.111.00064 23172927
Paton, J. F. et al. The carotid body as a therapeutic target for the treatment of sympathetically mediated diseases. Hypertension 61, 5–13 (2013).23172927
465. Pauza AG GLP1R attenuates sympathetic response to high glucose via carotid body inhibition Circ. Res. 2022 130 694 707 10.1161/CIRCRESAHA.121.319874 35100822
Pauza, A. G. et al. GLP1R attenuates sympathetic response to high glucose via carotid body inhibition. Circ. Res. 130, 694–707 (2022).35100822
466. Paton JF Revelations about carotid body function through its pathological role in resistant hypertension Curr. Hypertens. Rep. 2013 15 273 280 10.1007/s11906-013-0366-z 23828147
Paton, J. F. et al. Revelations about carotid body function through its pathological role in resistant hypertension. Curr. Hypertens. Rep. 15, 273–280 (2013).23828147
467. Marso SP Semaglutide and cardiovascular outcomes in patients with type 2 diabetes N. Engl. J. Med 2016 375 1834 1844 10.1056/NEJMoa1607141 27633186
Marso, S. P. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).27633186
468. Hernandez AF Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial Lancet 2018 392 1519 1529 10.1016/S0140-6736(18)32261-X 30291013
Hernandez, A. F. et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 392, 1519–1529 (2018).30291013
469. Ban K Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways Circulation 2008 117 2340 2350 10.1161/CIRCULATIONAHA.107.739938 18427132
Ban, K. et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117, 2340–2350 (2008).18427132
470. Kosiborod, M. N. et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N. Engl. J. Med. 389, 1069–1084 (2023).
471. McMurray JJV Dapagliflozin in patients with heart failure and reduced ejection fraction N. Engl. J. Med. 2019 381 1995 2008 10.1056/NEJMoa1911303 31535829
McMurray, J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381, 1995–2008 (2019).31535829
472. Zelniker TA SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials Lancet 2019 393 31 39 10.1016/S0140-6736(18)32590-X 30424892
Zelniker, T. A. et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393, 31–39 (2019).30424892
473. Packer M Cardiovascular and renal outcomes with empagliflozin in heart failure N. Engl. J. Med. 2020 383 1413 1424 10.1056/NEJMoa2022190 32865377
Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424 (2020).32865377
474. Verma S McMurray JJV SGLT2 inhibitors and mechanisms of cardiovascular benefit: A state-of-the-art review Diabetologia 2018 61 2108 2117 10.1007/s00125-018-4670-7 30132036
Verma, S. & McMurray, J. J. V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: A state-of-the-art review. Diabetologia 61, 2108–2117 (2018).30132036
475. Sano M A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity J. Cardiol. 2018 71 471 476 10.1016/j.jjcc.2017.12.004 29415819
Sano, M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J. Cardiol. 71, 471–476 (2018).29415819
476. Dwibedi C Randomized open-label trial of semaglutide and dapagliflozin in patients with type 2 diabetes of different pathophysiology Nat. Metab. 2024 6 50 60 10.1038/s42255-023-00943-3 38177805
Dwibedi, C. et al. Randomized open-label trial of semaglutide and dapagliflozin in patients with type 2 diabetes of different pathophysiology. Nat. Metab. 6, 50–60 (2024).38177805
477. Zannad F SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials Lancet 2020 396 819 829 10.1016/S0140-6736(20)31824-9 32877652
Zannad, F. et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 396, 819–829 (2020).32877652
478. Wright AK Primary prevention of cardiovascular and heart failure events With SGLT2 inhibitors, GLP-1 receptor agonists, and their combination in type 2 diabetes Diab Care 2022 45 909 918 10.2337/dc21-1113
Wright, A. K. et al. Primary prevention of cardiovascular and heart failure events With SGLT2 inhibitors, GLP-1 receptor agonists, and their combination in type 2 diabetes. Diab Care 45, 909–918 (2022).
479. Panico C Pathophysiological basis of the cardiological benefits of SGLT-2 inhibitors: a narrative review Cardiovasc Diabetol. 2023 22 164 10.1186/s12933-023-01855-y 37391739
Panico, C. et al. Pathophysiological basis of the cardiological benefits of SGLT-2 inhibitors: a narrative review. Cardiovasc Diabetol. 22, 164 (2023).37391739
480. Giugliano D GLP-1 receptor agonists vs. SGLT-2 inhibitors: the gap seems to be leveling off Cardiovasc Diabetol. 2021 20 205 10.1186/s12933-021-01400-9 34641876
Giugliano, D. et al. GLP-1 receptor agonists vs. SGLT-2 inhibitors: the gap seems to be leveling off. Cardiovasc Diabetol. 20, 205 (2021).34641876
481. Natali A Nesti L Tricò D Ferrannini E Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence Cardiovasc Diabetol. 2021 20 196 10.1186/s12933-021-01385-5 34583699
Natali, A., Nesti, L., Tricò, D. & Ferrannini, E. Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence. Cardiovasc Diabetol. 20, 196 (2021).34583699
482. Jhund PS SGLT2 inhibitors and heart failure with preserved ejection fraction Heart Fail Clin. 2022 18 579 586 10.1016/j.hfc.2022.03.010 36216487
Jhund, P. S. SGLT2 inhibitors and heart failure with preserved ejection fraction. Heart Fail Clin. 18, 579–586 (2022).36216487
483. Lu H Shang P Zhou D SGLT2 inhibitors for patients with heart failure with preserved ejection fraction in China: a cost-effectiveness study Front Pharm. 2023 14 1155210 10.3389/fphar.2023.1155210
Lu, H., Shang, P. & Zhou, D. SGLT2 inhibitors for patients with heart failure with preserved ejection fraction in China: a cost-effectiveness study. Front Pharm. 14, 1155210 (2023).
484. Belli, M. et al. Treatment of HFpEF beyond the SGLT2-Is: Does the addition of GLP-1 RA improve cardiometabolic risk and outcomes in diabetic patients? Int. J. Mol. Sci. 23, 14598 (2022).
485. Wan, W. et al. GLP-1R signaling and functional molecules in incretin therapy. Molecules. 28, 751 (2023).
486. Kolczynska K Loza-Valdes A Hawro I Sumara G Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review Lipids Health Dis. 2020 19 113 10.1186/s12944-020-01286-8 32466765
Kolczynska, K., Loza-Valdes, A., Hawro, I. & Sumara, G. Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review. Lipids Health Dis. 19, 113 (2020).32466765
487. Carvalho T Efruxifermin combined with a GLP-1 receptor agonist reduces liver fat in NASH Nat. Med. 2023 29 1881 10.1038/d41591-023-00055-1 37340082
Carvalho, T. Efruxifermin combined with a GLP-1 receptor agonist reduces liver fat in NASH. Nat. Med. 29, 1881 (2023).37340082
488. Burcelin R The incretins: a link between nutrients and well-being Br. J. Nutr. 2005 93 S147 156 10.1079/BJN20041340 15877888
Burcelin, R. The incretins: a link between nutrients and well-being. Br. J. Nutr. 93, S147–156 (2005).15877888
489. Esterházy D Mucida D Gut immune cells have a role in food metabolism Nature 2019 566 49 50 10.1038/d41586-019-00235-5 30710125
Esterházy, D. & Mucida, D. Gut immune cells have a role in food metabolism. Nature 566, 49–50 (2019).30710125
490. Ma X Guan Y Hua X Glucagon-like peptide 1-potentiated insulin secretion and proliferation of pancreatic β-cells J. Diab 2014 6 394 402 10.1111/1753-0407.12161
Ma, X., Guan, Y. & Hua, X. Glucagon-like peptide 1-potentiated insulin secretion and proliferation of pancreatic β-cells. J. Diab 6, 394–402 (2014).
491. Ranganath LR Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 J. Clin. Pathol. 2008 61 401 409 10.1136/jcp.2006.043232 18375745
Ranganath, L. R. Incretins: pathophysiological and therapeutic implications of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. J. Clin. Pathol. 61, 401–409 (2008).18375745
492. Andreasen CR Andersen A Vilsbøll T The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease Diabetologia 2023 66 1846 1858 10.1007/s00125-023-05966-9 37498367
Andreasen, C. R., Andersen, A. & Vilsbøll, T. The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease. Diabetologia 66, 1846–1858 (2023).37498367
493. Dutta D Impact of semaglutide on biochemical and radiologic measures of metabolic-dysfunction associated fatty liver disease across the spectrum of glycaemia: A meta-analysis Diab Metab. Syndr. 2022 16 102539 10.1016/j.dsx.2022.102539
Dutta, D. et al. Impact of semaglutide on biochemical and radiologic measures of metabolic-dysfunction associated fatty liver disease across the spectrum of glycaemia: A meta-analysis. Diab Metab. Syndr. 16, 102539 (2022).
494. Sheka AC Nonalcoholic Steatohepatitis: A Review Jama 2020 323 1175 1183 10.1001/jama.2020.2298 32207804
Sheka, A. C. et al. Nonalcoholic Steatohepatitis: A Review. Jama 323, 1175–1183 (2020).32207804
495. Pouwels S Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss BMC Endocr. Disord. 2022 22 63 10.1186/s12902-022-00980-1 35287643
Pouwels, S. et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr. Disord. 22, 63 (2022).35287643
496. Traussnigg S Challenges and management of liver cirrhosis: Practical issues in the therapy of patients with cirrhosis due to NAFLD and NASH Dig. Dis. 2015 33 598 607 10.1159/000375353 26159280
Traussnigg, S. et al. Challenges and management of liver cirrhosis: Practical issues in the therapy of patients with cirrhosis due to NAFLD and NASH. Dig. Dis. 33, 598–607 (2015).26159280
497. Westfall E Jeske R Bader AR Nonalcoholic fatty liver disease: Common questions and answers on diagnosis and management Am. Fam. Physician 2020 102 603 612 33179890
Westfall, E., Jeske, R. & Bader, A. R. Nonalcoholic fatty liver disease: Common questions and answers on diagnosis and management. Am. Fam. Physician 102, 603–612 (2020).33179890
498. Pafili K Roden M Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans Mol. Metab. 2021 50 101122 10.1016/j.molmet.2020.101122 33220492
Pafili, K. & Roden, M. Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans. Mol. Metab. 50, 101122 (2021).33220492
499. Patel Chavez C Cusi K Kadiyala S The emerging role of glucagon-like peptide-1 receptor agonists for the management of NAFLD J. Clin. Endocrinol. Metab. 2022 107 29 38 10.1210/clinem/dgab578 34406410
Patel Chavez, C., Cusi, K. & Kadiyala, S. The emerging role of glucagon-like peptide-1 receptor agonists for the management of NAFLD. J. Clin. Endocrinol. Metab. 107, 29–38 (2022).34406410
500. Ghazanfar H Role of glucagon-like peptide-1 receptor agonists in the management of non-alcoholic steatohepatitis: A clinical review article Cureus 2021 13 e15141 34164242
Ghazanfar, H. et al. Role of glucagon-like peptide-1 receptor agonists in the management of non-alcoholic steatohepatitis: A clinical review article. Cureus 13, e15141 (2021).34164242
501. Kořínková L Pathophysiology of NAFLD and NASH in experimental models: The role of food intake regulating peptides Front Endocrinol. (Lausanne) 2020 11 597583 10.3389/fendo.2020.597583 33324348
Kořínková, L. et al. Pathophysiology of NAFLD and NASH in experimental models: The role of food intake regulating peptides. Front Endocrinol. (Lausanne) 11, 597583 (2020).33324348
502. Dai Y Comparison of the efficacy of glucagon-like peptide-1 receptor agonists in patients with metabolic associated fatty liver disease: Updated systematic review and meta-analysis Front Endocrinol. (Lausanne) 2020 11 622589 10.3389/fendo.2020.622589 33664710
Dai, Y. et al. Comparison of the efficacy of glucagon-like peptide-1 receptor agonists in patients with metabolic associated fatty liver disease: Updated systematic review and meta-analysis. Front Endocrinol. (Lausanne) 11, 622589 (2020).33664710
503. Petrovic A The role of GLP1-RAs in direct modulation of lipid metabolism in hepatic tissue as determined using in vitro models of NAFLD Curr. Issues Mol. Biol. 2023 45 4544 4556 10.3390/cimb45060288 37367037
Petrovic, A. et al. The role of GLP1-RAs in direct modulation of lipid metabolism in hepatic tissue as determined using in vitro models of NAFLD. Curr. Issues Mol. Biol. 45, 4544–4556 (2023).37367037
504. Finck BN Targeting metabolism, insulin resistance, and diabetes to treat nonalcoholic steatohepatitis Diabetes 2018 67 2485 2493 10.2337/dbi18-0024 30459251
Finck, B. N. Targeting metabolism, insulin resistance, and diabetes to treat nonalcoholic steatohepatitis. Diabetes 67, 2485–2493 (2018).30459251
505. Nogueira JP Cusi K Role of insulin resistance in the development of nonalcoholic fatty liver disease in people with type 2 diabetes: From bench to patient care Diab Spectr. 2024 37 20 28 10.2337/dsi23-0013
Nogueira, J. P. & Cusi, K. Role of insulin resistance in the development of nonalcoholic fatty liver disease in people with type 2 diabetes: From bench to patient care. Diab Spectr. 37, 20–28 (2024).
506. Song C Long X He J Huang Y Recent evaluation about inflammatory mechanisms in nonalcoholic fatty liver disease Front Pharm. 2023 14 1081334 10.3389/fphar.2023.1081334
Song, C., Long, X., He, J. & Huang, Y. Recent evaluation about inflammatory mechanisms in nonalcoholic fatty liver disease. Front Pharm. 14, 1081334 (2023).
507. Myint M Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions J. Transl. Med 2023 21 757 10.1186/s12967-023-04627-0 37884933
Myint, M. et al. Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions. J. Transl. Med 21, 757 (2023).37884933
508. Fang C The AMPK pathway in fatty liver disease Front Physiol. 2022 13 970292 10.3389/fphys.2022.970292 36203933
Fang, C. et al. The AMPK pathway in fatty liver disease. Front Physiol. 13, 970292 (2022).36203933
509. Long JK Dai W Zheng YW Zhao S P. miR-122 promotes hepatic lipogenesis via inhibiting the LKB1/AMPK pathway by targeting Sirt1 in non-alcoholic fatty liver disease Mol. Med. 2019 25 26 10.1186/s10020-019-0085-2 31195981
Long, J. K., Dai, W., Zheng, Y. W. & Zhao, S. P. miR-122 promotes hepatic lipogenesis via inhibiting the LKB1/AMPK pathway by targeting Sirt1 in non-alcoholic fatty liver disease. Mol. Med. 25, 26 (2019).31195981
510. Aslam, M. & Ladilov, Y. Emerging role of cAMP/AMPK signaling. Cells 11, 308 (2022).
511. Targher G Mantovani A Byrne CD Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease Lancet Gastroenterol. Hepatol. 2023 8 179 191 10.1016/S2468-1253(22)00338-7 36620987
Targher, G., Mantovani, A. & Byrne, C. D. Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease. Lancet Gastroenterol. Hepatol. 8, 179–191 (2023).36620987
512. Wang XC Gusdon AM Liu H Qu S Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation World J. Gastroenterol. 2014 20 14821 14830 10.3748/wjg.v20.i40.14821 25356042
Wang, X. C., Gusdon, A. M., Liu, H. & Qu, S. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World J. Gastroenterol. 20, 14821–14830 (2014).25356042
513. Nevola, R. et al. GLP-1 Receptor agonists in non-alcoholic fatty liver disease: Current evidence and future perspectives. Int. J. Mol. Sci. 24, 1703 (2023).
514. Sofogianni A Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update World J. Hepatol. 2020 12 493 505 10.4254/wjh.v12.i8.493 32952876
Sofogianni, A. et al. Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update. World J. Hepatol. 12, 493–505 (2020).32952876
515. Rahman S Islam R Mammalian Sirt1: insights on its biological functions Cell Commun. Signal 2011 9 11 10.1186/1478-811X-9-11 21549004
Rahman, S. & Islam, R. Mammalian Sirt1: insights on its biological functions. Cell Commun. Signal 9, 11 (2011).21549004
516. Li X SIRT1 and energy metabolism Acta Biochim Biophys. Sin. (Shanghai) 2013 45 51 60 10.1093/abbs/gms108 23257294
Li, X. SIRT1 and energy metabolism. Acta Biochim Biophys. Sin. (Shanghai) 45, 51–60 (2013).23257294
517. Varghese B SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism J. Transl. Med. 2023 21 627 10.1186/s12967-023-04440-9 37715252
Varghese, B. et al. SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism. J. Transl. Med. 21, 627 (2023).37715252
518. Kojima, M. et al. Glucagon-like peptide-1 receptor agonist prevented the progression of hepatocellular carcinoma in a mouse model of nonalcoholic Steatohepatitis. Int. J. Mol. Sci. 21, 5722 (2020).
519. Ma B High glucose promotes the progression of colorectal cancer by activating the BMP4 signaling and inhibited by glucagon-like peptide-1 receptor agonist BMC Cancer 2023 23 594 10.1186/s12885-023-11077-w 37370018
Ma, B. et al. High glucose promotes the progression of colorectal cancer by activating the BMP4 signaling and inhibited by glucagon-like peptide-1 receptor agonist. BMC Cancer 23, 594 (2023).37370018
520. Zhao H Activation of glucagon-like peptide-1 receptor inhibits tumourigenicity and metastasis of human pancreatic cancer cells via PI3K/Akt pathway Diab Obes. Metab. 2014 16 850 860 10.1111/dom.12291
Zhao, H. et al. Activation of glucagon-like peptide-1 receptor inhibits tumourigenicity and metastasis of human pancreatic cancer cells via PI3K/Akt pathway. Diab Obes. Metab. 16, 850–860 (2014).
521. Nagendra L Bg H Sharma M Dutta D Semaglutide and cancer: A systematic review and meta-analysis Diab Metab. Syndr. 2023 17 102834 10.1016/j.dsx.2023.102834
Nagendra, L., Bg, H., Sharma, M. & Dutta, D. Semaglutide and cancer: A systematic review and meta-analysis. Diab Metab. Syndr. 17, 102834 (2023).
522. Yen FS Effects of glucagon-like peptide-1 receptor agonists on liver-related and cardiovascular mortality in patients with type 2 diabetes BMC Med. 2024 22 8 10.1186/s12916-023-03228-4 38172833
Yen, F. S. et al. Effects of glucagon-like peptide-1 receptor agonists on liver-related and cardiovascular mortality in patients with type 2 diabetes. BMC Med. 22, 8 (2024).38172833
523. Arvanitakis, K., Koufakis, T., Kotsa, K. & Germanidis, G. How far beyond diabetes can the benefits of glucagon-like peptide-1 receptor agonists go? A review of the evidence on their effects on hepatocellular carcinoma. Cancers (Basel). 14, 4651 (2022).
524. Körner M Stöckli M Waser B Reubi JC GLP-1 receptor expression in human tumors and human normal tissues: Potential for in vivo targeting J. Nucl. Med. 2007 48 736 743 10.2967/jnumed.106.038679 17475961
Körner, M., Stöckli, M., Waser, B. & Reubi, J. C. GLP-1 receptor expression in human tumors and human normal tissues: Potential for in vivo targeting. J. Nucl. Med. 48, 736–743 (2007).17475961
525. Hunt, J. E., Holst, J. J., Jeppesen, P. B. & Kissow, H. GLP-1 and intestinal diseases. Biomedicines. 9, 383 (2021).
526. Alobaid, S. M. et al. Liraglutide attenuates diabetic cardiomyopathy via the ILK/PI3K/AKT/PTEN signaling pathway in rats with streptozotocin-induced type 2 diabetes mellitus. Pharmaceuticals (Basel). 17, 374 (2024).
527. Yang Z GLP-1 receptor agonist-associated tumor adverse events: A real-world study from 2004 to 2021 based on FAERS Front Pharmacol. 2022 13 925377 10.3389/fphar.2022.925377 36386208
Yang, Z. et al. GLP-1 receptor agonist-associated tumor adverse events: A real-world study from 2004 to 2021 based on FAERS. Front Pharmacol. 13, 925377 (2022).36386208
