
==== Front
Zhong Nan Da Xue Xue Bao Yi Xue Ban
Zhong Nan Da Xue Xue Bao Yi Xue Ban
zndx
Journal of Central South University Medical Sciences
1672-7347
中南大学出版社 湖南省长沙市湘雅路110号湘雅医学院

39311778
1672-7347(2024)06-0832-07
10.11817/j.issn.1672-7347.2024.240113
240113
Topics on Endocrine and Metabolic Disease
Nesfatin-1与糖代谢关系的研究进展
Research progress on the relationship between Nesfatin-1 and glucose metabolismhttp://orcid.org/0009-0006-0119-868X
曹 云婷 CAO Yunting
http://orcid.org/0000-0001-6607-6137
王 玮 WANG Wei
包头医学院第一附属医院内分泌科，内蒙古自治区 包头 014010
Department of Endocrinology, First Affiliated Hospital of Baotou Medical College, Baotou Inner Mongolia Autonomous Region 014010 China
郭 征 executive-editor
王玮，Email: vvhappy521@163.com, ORCID: 0000-0001-6607-6137
曹云婷，Email: 767007288@qq.com, ORCID: 0009-0006-0119-868X

28 6 2024
49 6 832838
28 2 2024
©Journal of Central South University (Medical Science). All rights reserved.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ 开放获取(Open access)：本文遵循知识共享许可协议，允许第三方用户按照署名-非商业性使用-禁止演绎4.0(CC BY-NC-ND 4.0)的方式，在任何媒介以任何形式复制、传播本作品(https://creativecommons.org/licenses/by-nc-nd/4.0/)。
Nesfatin-1是一种神经肽类激素，已知的生物学作用包括抑制食物摄入、调节血糖血脂代谢、促进细胞凋亡、抗炎、抗肿瘤等。糖代谢是机体能量来源的重要途径。目前的研究已证实Nesfatin-1可通过抑制摄食、调节酶活性、改善胰岛素抵抗等途径影响糖代谢，但是结论并不完全一致。探讨Nesfatin-1与糖代谢的关系可为糖代谢障碍相关疾病的诊断和治疗提供新的思路。

Nesfatin-1 is a neuropeptide hormone known for its biological functions, including inhibiting food intake, regulating glucose and lipid metabolism, promoting apoptosis, and providing anti-inflammatory and anti-tumor effects. Glucose metabolism is a crucial pathway for the body’s energy supply. Current research has demonstrated that Nesfatin-1 can affect glucose metabolism through various mechanisms, such as inhibiting food intake, regulating enzyme activity, and improving insulin resistance, though the findings are not entirely consistent. Investigating the relationship between Nesfatin-1 and glucose metabolism may offer new insights into the diagnosis and treatment of diseases related to glucose metabolism disorders.

Nesfatin-1
糖代谢
糖尿病
抑制摄食
Nesfatin-1
glucose metabolism
diabetes mellitus
inhibiting food intake
内蒙古自治区高等学校科学研究项目NJZY21058┫。This work was supported by the Scientific Research Project of Higher Education Institutions in Inner Mongolia Autonomous Region China ┣NJZY21058
==== Body
pmc2006年由日本学者Oh-I等[1]首次在实验大鼠下丘脑中发现的分泌性多肽Nesfatin-1是一种与黑皮质素相关的饱腹感分子，参与糖代谢的调节过程。

1 Nesfatin-1概述

1.1 Nesfatin-1的发现及结构

研究[1]发现：在SQ-5细胞中，过氧化物酶体增殖物激活受体(peroxisome proliferator activated receptor，PPAR)γ激动剂曲格列酮可激活9种基因，其中核组蛋白2(nucleobindin 2，NUCB2)的5’端非翻译区DNA片段受其调节尤为明显。NUCB2在激素原转化酶作用下被剪切为Nesfatin-1、Nesfatin-2、Nesfatin-3共3个片段。向大鼠侧脑室注入Nesfatin-1可引起体重下降，且其摄食量与Nesfatin-1的注入剂量呈负相关，而其他2个片段无此作用。Nesfatin-1作为一种摄食调节因子，是由82个氨基酸组成的多肽，包含N端序列(N23)、中段序列(M30)和C端序列(C29)[2]。

1.2 Nesfatin-1的分布

Nesfatin-1在哺乳动物、鱼类和鸟类中广泛存在。Nesfatin-1的氨基酸序列在各类动物中高度保守且具有高度同源性，提示其可能与生理结构和功能相关[3]。Nesfatin-1主要分布在中枢神经系统以及消化道、肺、心肌、脂肪组织和生殖腺等组织细胞中[4-5]。在中枢神经系统中，Nesfatin-1主要通过下丘脑的不同核发挥抑制摄食的作用[6]；在消化系统中，Nesfatin-1与肠道微生物相互作用，调节肠道屏障结构，从而间接影响食物的消化、吸收和代谢[7]。

1.3 Nesfatin-1的主要生理功能

下丘脑是摄食和内分泌调节的中枢，胃肠道影响食物的消化和吸收，Nesfatin-1广泛分布于下丘脑和胃肠道，故其与内分泌、摄食及血糖代谢关系密切[5]。目前已证实Nesfatin-1具有以下生理功能及作用：1)抑制食物摄入，调节血糖代谢。腹腔注射Nesfatin-1能够减少进食量，连续注射6 d可抑制体重的增长[8]。研究[9]发现肥胖患者内脏脂肪组织中Nesfatin-1的水平高于正常体重者。向大鼠体内注射Nesfatin-1抗体会引起大鼠食欲增加[10]。但是，到目前为止，关于血清Nesfatin-1水平与糖代谢及糖尿病患者血糖的关系仍然没有定论。2)调节内分泌轴。在大鼠侧脑室内注入Nesfatin-1后，血液中的生长激素释放激素、生长激素、生长抑素水平均下降。Nesfatin-1水平与新生儿体重呈负相关，其可能参与生长发育及激素的调控[11]。Nesfatin-1可改善雌激素缺乏引起的骨强度降低[12]。3)抗炎、抗肿瘤。Nesfatin-1在股骨头坏死患者中较正常人有所上升[13]。Nesfatin-1在肿瘤发生和发展过程中也起关键作用[14]。胃癌患者癌组织和血清中Nesfatin-1水平均上调[15]。4)调控精神心理，治疗精神及心理疾病。Liu等[16]研究发现在急性应激状态下大鼠下丘脑中Nesfatin-1表达上调。5)协助呼吸系统疾病的诊断。阻塞性睡眠呼吸暂停综合征患者体内Nesfatin-1较正常人群升高[17]。6)保护心脏及评估冠状动脉性心脏病严重程度。Sharifi等[18]研究发现Nesfatin-1有保护心脏的作用。此外，有研究[19]发现Nesfatin-1与冠状动脉性心脏病严重程度呈负相关。

综上，Nesfatin-1的生理作用众多，但其分布决定了其经典作用是对摄食中枢的抑制，近年越来越多的研究关注了其在外周对糖代谢的调节作用。

2 Nesfatin-1与糖代谢的关系

2.1 糖代谢和糖尿病

葡萄糖及糖原是机体主要的能量来源，对维持生理功能至关重要[20]。糖代谢主要通过血液循环将葡萄糖输送到全身各器官，涉及有氧氧化、无氧酵解、磷酸戊糖途径，包括合成代谢和分解代谢。胰岛素和胰高血糖素是调节糖代谢的最主要激素，其失衡可引起血糖升高或降低，导致代谢内分泌异常。代谢内分泌疾病受环境、遗传和免疫等多因素共同影响[21]。其中1型糖尿病是由于免疫介导胰岛β细胞的破坏，引起胰岛素分泌不足；2型糖尿病则主要以胰岛素抵抗为主[22]，为糖尿病的主要类型[23]。鉴于长期糖代谢异常的危害及较低的糖代谢异常早期诊断率[24]，有必要研究新的早期诊断糖代谢异常的生物学标志物。

2.2 Nesfatin-1水平与血糖的关系

Nesfatin-1调节糖代谢的具体机制仍未阐明。Nesfatin-1可能通过调节下丘脑黑皮质素信号通路，参与胃肠功能的生理调节，从而影响食欲，减少食物摄入，降低血糖[25]。探究机体Nesfatin-1水平与血糖水平关系的研究结果并不一致。有研究[26]结果显示血清Nesfatin-1水平在新近诊断的2型糖尿病患者中有所升高，而其他研究[27-28]则显示出相反的结果，这可能是因为Nesfatin-1在2型糖尿病初期起代偿性保护作用，因此水平升高。另一项荟萃分析[29]结果显示：新诊断的糖尿病患者血清Nesfatin-1水平升高，但在药物治疗后会有所下降；若未经治疗的2型糖尿病患者血清Nesfatin-1水平呈下降趋势，则提示患者血糖、血脂水平较高，病情有恶化趋向。孟琦[30]等研究发现2型糖尿病患者组血清Nesfatin-1水平低于健康对照组。另有研究[31]结果亦显示2型糖尿病患者的血浆Nesfatin-1水平明显低于健康受试者和1型糖尿病患者。

2.3 Nesfatin-1调节糖代谢的途径

Nesfatin-1主要通过调节下丘脑、胃肠道、胰腺及棕色脂肪组织(brown adipose tissue，BAT)影响糖代谢(图1)。

图1 Nesfatin-1调节糖代谢的途径及机制

Figure 1 Pathways and mechanisms by which Nesfatin-1 regulates glucose metabolism TRH: Thyrotropin-releasing hormone; CRH: Corticotropin-releasing hormone.

2.3.1 促进下丘脑中激素的释放

早期研究[32]已证实Nesfatin-1刺激下丘脑释放更多的促肾上腺皮质激素释放激素(corticotropin-releasing hormone，CRH)和促甲状腺激素释放激素(thyrotropin-releasing hormone，TRH)，发挥影响食欲的作用，最终引起血糖下降。向哺乳动物及鱼类的侧脑室中注入Nesfatin-1后，与对照组相比，实验组在最初24 h内的进食量明显下降，在皮下注射后观察到其食欲抑制作用可以持续约14 h，连续给药6 d后体重下降，且下降速度与剂量成正比[33]。Nesfatin-1的抑制摄食作用在使用CRH受体拮抗剂、TRH受体拮抗剂的小鼠有所减弱；在结节乳头体核(tuberomammillary nucleus，TMN)的组胺神经元细胞膜上存在CRH受体1和TRH受体2，故考虑Nesfatin-1可能通过CRH神经元、TRH神经元及TMN组胺神经元抑制食物的摄入。综上，Nesfatin-1可促进下丘脑激素释放，产生抑制摄食的效应，从而减少食物摄入，降低血糖水平。今后可进一步研究Nesfatin-1对下丘脑其他激素的调节机制。

2.3.2 减少胃酸分泌，降低食欲

Nesfatin-1除表达于中枢系统，还在外周表达并发挥作用。Nesfatin-1在外周的作用可能与钙离子刺激引起胃迷走神经传入神经元兴奋有关，通过减慢胃排空导致胃持续扩张而减少摄食，且胃排空速度随Nesfatin-1浓度增加而降低。研究[34]发现：向大鼠脑室内注射Nesfatin-1后，2-脱氧-D-葡萄糖介导的胃酸分泌减少，且与Nesfatin-1的注射剂量成正比，但是基础胃酸分泌不受影响。中枢系统的Nesfatin-1可通过兴奋中枢迷走神经，减少胃酸分泌，减慢胃肠蠕动的恢复，进而影响糖代谢。Özdemir-Kumral等[35]研究发现：中枢神经系统的Nesfatin-1可通过胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)受体、胆囊收缩素(cholecystokinin，CCK)受体参与胃排空的延迟。Kentish等[36]在有关胃动力学的研究中发现：Nesfatin-1一方面通过增加胃黏膜上受体的机械敏感性而减慢胃排空，降低食欲；另一方面通过减少胃窦的活动，增加十二指肠Ⅲ期的收缩电位的时长，进而减缓胃肠道蠕动，降低食欲，减少食物摄入，最终影响糖代谢。综上，Nesfatin-1可调节胃肠功能，今后可进一步研究Nesfatin-1的作用靶点及其作用机制。

2.3.3 增加胰岛素分泌

Gonzalez等[37]发现：给予Nesfatin-1处理的大鼠在口服葡萄糖耐量试验(oral glucose tolerance test，OGTT)期间循环中的胰岛素水平高于对照。当机体的血糖升高后，胰岛β细胞会分泌更多的Nesfatin-1[38]。胰岛素和Nesfatin-1可同时表达于胰腺β细胞。体外研究[39]结果显示：用Nesfatin-1处理高糖孵育的小鼠离体胰岛β细胞后，胰岛素分泌增加，而对低糖及常规孵化的胰岛β细胞的胰岛素分泌无明显影响。动物实验[39]研究发现NUCB2的基因表达与胰岛素分泌能力呈正相关，其降血糖作用可能具有胰岛素依赖性[39]。Nakata等[40]的研究发现：Nesfatin-1可通过激活钙离子通道，调节胰岛β细胞内钙离子水平，增加胰岛素分泌，并增加肝脏对胰岛素的敏感性，促进糖脂代谢，加强胰岛素对肝糖异生的抑制并减少肝糖输出，降低血浆内葡萄糖浓度。这也证明了Nesfatin-1的降血糖作用具有胰岛素依赖性。Nesfatin-1可活化信号转导通路，增加肥胖模型小鼠的胰岛素敏感性，推测Nesfatin-1与机体的糖脂代谢及胰岛素抵抗有关[41-42]。Nesfatin-1还可通过促进胰岛素受体与其底物相结合，激活蛋白酶、腺苷酶等酶相关信号通路，增加肝脏对胰岛素的敏感性，提高葡萄糖的利用率，减轻胰岛素抵抗，促进糖代谢[43]。Ravussin等[44]研究发现：NUCB2缺乏会增加核因子κB(nuclear factor kappa-B，NF-κB)依赖的巨噬细胞炎症因子如白细胞介素-1β(interleukin-1β，IL-1β)、肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)、巨噬细胞炎性蛋白-1α(macrophage inflammatory protein 1α，MIP-1α)的表达，导致肥胖患者胰岛素抵抗。综上，Nesfatin-1与糖代谢之间的密切关联已得到证实，但还需要更多的研究去探索更加准确的调控机制。

2.3.4 调节糖代谢中酶的活性

在动物实验[45]中，向大鼠第三脑室注射Nesfatin-1后，肝糖原的生成明显减少，肌糖原的分解增加，正常饮食及高脂饮食喂养的大鼠肝脏中磷酸烯醇式丙酮酸羧激酶(phosphoenolpyruvate carboxykinase，PEPCK)的活性降低。Nesfatin-1可激活AMP活化的蛋白质激酶(AMP-activated protein kinase，AMPK)-沉默信息调节因子1(silent information regulator of transcription 1，SIRT1)，增强葡萄糖转运蛋白的转录和易位，导致胰岛素依赖的葡萄糖摄取量增加。此外，Nesfatin-1还可通过抑制磷酸果糖激酶(phosphofructokinase，PFK)促进葡萄糖的分解代谢。Wu等[46]发现：激活大鼠中枢神经系统的Nesfatin-1后，其食物摄取量以及肝糖原的利用均明显增加；敲除大鼠下丘脑的Nesfatin-1基因会导致其肝糖原的转化发生显著变化；下丘脑Nesfatin-1的表达降低，可引起哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)磷酸化水平下调和信号转导与转录激活因子(signal transducers and activators of transcription，STAT)3作用减弱；向中枢神经系统注射Nesfatin-1可使mTOR复合体1(mTOR complex 1，mTORC1)通路上的缺氧诱导因子(hypoxia inducible factor-1α，HIF1α)翻译增加，从而引起PFK等酶的表达增加，影响糖代谢。综上，Nesfatin-1通过影响糖代谢中酶调节糖代谢，今后可进一步研究其分子调控机制。

2.3.5 诱导BAT产热，增加肝脏葡萄糖生成

Nesfatin-1通过调控体温参与糖代谢的过程。有研究[47]证实Nesfatin-1诱导BAT产生热量，使体温升高，组织代谢加快，肝脏葡萄糖生成增加。向大鼠侧脑室注射Nesfatin-1，2 d后大鼠体温持续超过生理体温，且昼夜波动较小。下丘脑释放的α-促黑素(α- melanocyte stimulating hormone，α-MSH)激活脊髓中央外侧柱(intermediolateral column of spinal cord，IML)的节前神经元中的黑皮质素受体4(melanocortin-4 receptor，MC4R)，刺激交感神经，增加活化解偶联蛋白1(uncoupling protein 1，UCP1)介导的BAT产热，升高体温，加速机体组织的糖代谢，最终增加肝脏中的葡萄糖生成。同时也有研究[48]表明Nesfatin-1可通过mTOR信号刺激BAT的生成，增加BAT中UCP-1的产生，其介导的产热作用增强，升高体温，加速代谢，因此反复向大脑中注入Nesfatin-1可减少大鼠体重的增加。今后可深入探讨Nesfatin-1对基础代谢的影响。

3 结 语

Nesfatin-1在中枢神经系统和外周组织中广泛分布，对多种生物学过程起作用，特别是与糖代谢密切相关。目前，研究重点主要集中在Nesfatin-1与能量摄入、肥胖、糖脂代谢、肿瘤、心血管疾病等的关系，但其准确作用及机制仍不完全清楚。除了已知的AMPK-SIRT1、mTOR等信号通路外，其他作用通路在这一过程中是否发挥作用尚需进一步验证。阐明Nesfatin-1的作用及其与糖代谢的相互关系对Nesfatin-1在临床诊断和治疗中的应用至关重要，仍需要进一步探索。

基金资助

内蒙古自治区高等学校科学研究项目(NJZY21058)。This work was supported by the Scientific Research Project of Higher Education Institutions in Inner Mongolia Autonomous Region, China (NJZY21058).

利益冲突声明

作者声称无任何利益冲突。

作者贡献

曹云婷 文献检索与整理，论文撰写与修改；王玮 论文指导、修改与审阅。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202406832.pdf

http://dx.chinadoi.cn/10.11817/j.issn.1672-7347.2024.240113
==== Refs
参考文献

1 Oh-I S , Shimizu H , Satoh T , Identification of nesfatin-1 as a satiety molecule in the hypothalamus[J]. Nature, 2006, 443 (7112 ): 709-712. 10.1038/nature05162. 17036007
2 Cheng HB , Zhu YF , Chen LJ , Nesfatin-1 alleviated lipopolysaccharide-induced acute lung injury through regulating inflammatory response associated with macrophages modulation[J]. J Cardiothorac Surg, 2022, 17 (1 ): 206. 10.1186/s13019-022-01952-1. 36008865
3 Rupp SK , Wölk E , Stengel A . Nesfatin-1 receptor: distribution, signaling and increasing evidence for a G protein-coupled receptor—A systematic review[J]. Front Endocrinol, 2021, 12 : 740174. 10.3389/fendo.2021.740174.
4 Dotania K , Tripathy M , Rai U . A comparative account of nesfatin-1 in vertebrates[J]. Gen Comp Endocrinol, 2021, 312 : 113874. 10.1016/j.ygcen.2021.113874. 34331938
5 Schalla MA , Unniappan S , Lambrecht NWG , NUCB2/nesfatin-1—Inhibitory effects on food intake, body weight and metabolism[J]. Peptides, 2020, 128 : 170308. 10.1016/j.peptides.2020.170308. 32229144
6 Xu YY , Chen FH . Antioxidant, anti-inflammatory and anti-apoptotic activities of nesfatin-1: a review[J]. J Inflamm Res, 2020, 13 : 607-617. 10.2147/JIR.S273446. 33061526
7 Kras K , Muszyński S , Tomaszewska E , Minireview: peripheral nesfatin-1 in regulation of the gut activity—15 years since the discovery[J]. Animals, 2022, 12 (1 ): 101. 10.3390/ani12010101. 35011207
8 Demirci Ş , Gün C . Zinc supplementation improved neuropeptide Y, nesfatin-1, leptin, C-reactive protein, and HOMA-IR of diet-induced obese rats[J]. Biol Trace Elem Res, 2022, 200 (9 ): 3996-4006. 10.1007/s12011-021-02987-6. 34708332
9 Caroleo M , Carbone EA , Arcidiacono B , Does NUCB2/nesfatin-1 influence eating behaviors in obese patients with binge eating disorder? toward a neurobiological pathway[J]. Nutrients, 2023, 15 (2 ): 348. 10.3390/nu15020348. 36678225
10 Jia FY , Li XL , Li TN , Role of nesfatin-1 in a rat model of visceral hypersensitivity[J]. World J Gastroenterol. 2013, 19 (22 ): 3487-3493. 10.3748/wjg.v19.i22.3487. 23801843
11 Serin S , Bakacak M , Ercan Ö , The evaluation of Nesfatin-1 levels in patients with and without intrauterine growth restriction[J]. J Matern Fetal Neonatal Med, 2016, 29 (9 ): 1409-1413. 10.3109/14767058.2015.1049524. 26043295
12 Skic A , Puzio I , Tymicki G , Effect of nesfatin-1 on rat humerus mechanical properties under quasi-static and impact loading conditions[J]. Materials, 2022, 15 (1 ): 333. 10.3390/ma15010333. 35009479
13 庞士龙, 王汉, 张志强, 等. 血浆Nesfatin-1、DKK-1水平与股骨头坏死的关系[J]. 检验医学, 2021, 36 (12 ): 1248-1252. 10.3969/j.issn.1673-8640.2021.012.011.
PANG Shilong , WANG Han , ZHANG Zhiqiang , Relationship between plasma Nesfatin-1 and DKK-1 levels and osteonecrosis of the femoral head[J]. Laboratory Medicine, 2021, 36 (12 ): 1248-1252. 10.3969/j.issn.1673-8640.2021.012.011.
14 Kmiecik AM , Dzięgiel P , Podhorska-Okołów M . Nucleobindin-2/nesfatin-1-a new cancer related molecule?[J]. Int J Mol Sci, 2021, 22 (15 ): 8313. 10.3390/ijms22158313. 34361082
15 Ren L , Bao DM , Wang LM , Nucleobindin-2/nesfatin-1 enhances the cell proliferation, migration, invasion and epithelial-mesenchymal transition in gastric carcinoma[J]. J Cell Mol Med, 2022, 26 (19 ): 4986-4994. 10.1111/jcmm.17522. 36065769
16 Liu M , Shen XL , Du XX , Plasma levels of nesfatin-1 as a new biomarker in depression in Asians: evidence from meta-analysis[J]. Biomarkers, 2020, 25 (3 ): 228-234. 10.1080/1354750X.2020.1736157. 32116029
17 刘亚男, 何宁, 勾璇 . 2型糖尿病合并阻塞性睡眠呼吸暂停低通气综合征患者血清Chemerin、Nesfatin-1、Obestatin的检测水平及意义[J]. 临床和实验医学杂志, 2021, 20 (24 ): 2614-2617. 10.3969/j.issn.1671-4695.2021.24.011.
LIU Yanan , HE Ning , GOU Xuan . Detection levels and significance of serum Chemerin, Nesfatin-1 and Obestatin in patients with type 2 diabetes mellitus complicated obstructive sleep apnea hypopnea syndrome[J]. Journal of Clinical and Experimental Medicine, 2021, 20 (24 ): 2614-2617. 10.3969/j.issn.1671-4695.2021.24.011.
18 Sharifi M , Nazarinia D , Ramezani F , Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model[J]. Mol Biol Rep, 2021, 48 (3 ): 2507-2518. 10.1007/s11033-021-06289-x. 33755849
19 Kadoglou NPE , Korakas E , Lampropoulos S , Plasma nesfatin-1 and DDP-4 levels in patients with coronary artery disease: Kozani study[J]. Cardiovasc Diabetol, 2021, 20 (1 ): 166. 10.1186/s12933-021-01355-x. 34389003
20 Li Q , Gui X , Zhang HR , Role of glucose metabolism in ocular angiogenesis (Review)[J]. Mol Med Rep, 2022, 26 (6 ): 363. 10.3892/mmr.2022.12880. 36281924
21 Tan SY , Mei Wong JL , Sim YJ , Type 1 and 2 diabetes mellitus: a review on current treatment approach and gene therapy as potential intervention[J]. Diabetes Metab Syndr, 2019, 13 (1 ): 364-372. 10.1016/j.dsx.2018.10.008. 30641727
22 Ren L , Cheng YX , Qin F . Herbal formula gegen-Qinlian decoction for type 2 diabetes mellitus: a meta-analysis of randomized controlled trials[J]. Evid Based Complement Alternat Med, 2020, 2020 : 3907920. 10.1155/2020/3907920. 33144868
23 王甜, 吴华, 刘娅萍 . 2型糖尿病合并大血管病变老年患者血清摄食抑制因子1、腓骨蛋白-1水平与血脂及胰岛素抵抗的关系[J]. 海南医学, 2022, 33 (19 ): 2483-2487. 10.3969/j.issn.1003-6350.2022.19.010.
WANG Tian , WU Hua , LIU Yaping . Relationship between serum nesfatin-1, Fibulin-1 levels and blood lipid, insulin resistance in elderly patients with type 2 diabetes mellitus complicated with macrovascular disease[J]. Hainan Medical Journal, 2022, 33 (19 ): 2483-2487. 10.3969/j.issn.1003-6350.2022.19.010.
24 Yin B , Bi YM , Fan GJ , Molecular mechanism of the effect of Huanglian Jiedu Decoction on type 2 diabetes mellitus based on network pharmacology and molecular docking[J]. J Diabetes Res, 2020, 2020 : 5273914. 10.1155/2020/5273914. 33134394
25 Nasri A , Unniappan S . Nucleobindin-derived nesfatin-1 and nesfatin-1-like peptide stimulate pro-opiomelanocortin synthesis in murine AtT-20 corticotrophs through the cAMP/PKA/CREB signaling pathway[J]. Mol Cell Endocrinol, 2021, 536 : 111401. 10.1016/j.mce.2021.111401. 34302909
26 Guo Y , Liao Y , Fang G , Increased nucleobindin-2 (NUCB2) transcriptional activity links the regulation of insulin sensitivity in Type 2 diabetes mellitus[J]. J Endocrinol Investig, 2013, 36 (10 ): 883-888. 10.3275/9000. 23765387
27 杨智茹, 李家婕, 刘文龙 . 血清nesfatin-1和apelin及HO-1水平与糖尿病视网膜病变严重程度的相关性[J]. 国际眼科杂志, 2023, 23 (11 ): 1865-1869. 10.3980/j.issn.1672-5123.2023.11.19.
YANG Zhiru , LI Jiajie , LIU Wenlong . Correlation between serum nesfatin-1, a pelin and HO-1 levels and the severity of diabetic retinopathy[J]. International Eye Science, 2023, 23 (11 ): 1865-1869. 10.3980/j.issn.1672-5123.2023.11.19.
28 Huang KK , Liang YL , Ma YT , The variation and correlation of serum adiponectin, nesfatin-1, IL-6, and TNF-α levels in prediabetes[J]. Front Endocrinol, 2022, 13 : 774272. 10.3389/fendo.2022.774272.
29 Zhai T , Li SZ , Fan XT , Circulating nesfatin-1 levels and type 2 diabetes: a systematic review and Meta-analysis[J]. J Diabetes Res, 2017, 2017 : 7687098. 10.1155/2017/7687098. 29445751
30 孟琦, 南晓利, 谭丽艳, 等. 肥胖抑制素、Nesfatin-1与2型糖尿病大血管病变相关性[J]. 医学理论与实践, 2023, 36 (6 ): 1020-1022. 10.19381/j.issn.1001-7585.2023.06.046.
MENG Qi , XiaoliNAN, TAN Liyan , Correlation between obesity inhibin, Nesfatin-1 and macroangiopathy in type 2 diabetes mellitus[J]. Journal of Medical Theory and Practice, 2023, 36 (6 ): 1020-1022. 10.19381/j.issn.1001-7585.2023.06.046.
31 Li QC , Wang HY , Chen X , Fasting plasma levels of nesfatin-1 in patients with type 1 and type 2 diabetes mellitus and the nutrient-related fluctuation of nesfatin-1 level in normal humans[J]. Regul Pept, 2010, 159 (1/2/3 ): 72-77. 10.1016/j.regpep.2009.11.003. 19896982
32 Stengel A , Goebel M , Wang LX , Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: differential role of corticotropin-releasing factor2 receptor[J]. Endocrinology, 2009, 150 (11 ): 4911-4919. 10.1210/en.2009-0578. 19797401
33 Shimizu H , Oh-I S , Okada S , Nesfatin-1: an overview and future clinical application[J]. Endocr J, 2009, 56 (4 ): 537-543. 10.1507/endocrj.k09e-117. 19461159
34 Xia ZF , Fritze DM , Li JY , Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats[J]. Am J Physiol Gastrointest Liver Physiol, 2012, 303 (5 ): G570-G577. 10.1152/ajpgi.00178.2012. 22723266
35 Özdemir-Kumral ZN , Koyuncuoğlu T , Arabacı-Tamer S , High-fat diet enhances gastric contractility, but abolishes nesfatin-1-induced inhibition of gastric emptying[J]. J Neurogastroenterol Motil, 2021, 27 (2 ): 265-278. 10.5056/jnm20206. 33795544
36 Kentish SJ , Li H , Frisby CL , Nesfatin-1 modulates murine gastric vagal afferent mechanosensitivity in a nutritional state dependent manner[J]. Peptides, 2017, 89 : 35-41. 10.1016/j.peptides.2017.01.005. 28087413
37 Gonzalez R , Reingold BK , Gao XD , Nesfatin-1 exerts a direct, glucose-dependent insulinotropic action on mouse islet β- and MIN6 cells[J]. J Endocrinol, 2011, 208 (3 ): R9-R16. 10.1530/JOE-10-0492. 21224288
38 李丽军 . Nesfatin-1和vaspin对妊娠期糖尿病的预测价值及与胰岛素抵抗的相关性[J]. 中国妇幼保健, 2021, 36 (7 ): 1487-1490. 10.19829/j.zgfybj.issn.1001-4411.2021.07.008.
LI Lijun . Predictive value of nesfatin-1 and vaspin in gestational diabetes mellitus and their correlation with insulin resistance[J]. Maternal and Child Health Care of China, 2021, 36 (7 ): 1487-1490. 10.19829/j.zgfybj.issn.1001-4411.2021.07.008.
39 Yang YF , Zhang BY , Nakata M , Islet β-cell-produced NUCB2/nesfatin-1 maintains insulin secretion and glycemia along with suppressing UCP-2 in β-cells[J]. J Physiol Sci, 2019, 69 (5 ): 733-739. 10.1007/s12576-019-00689-2. 31228099
40 Nakata M , Manaka K , Yamamoto S , Nesfatin-1 enhances glucose-induced insulin secretion by promoting Ca2+ influx through L-type channels in mouse islet β-cells[J]. Endocr J, 2011, 58 (4 ): 305-313. 10.1507/endocrj.k11e-056. 21325742
41 张文蓉, 王苏建, 史剑雷, 等. 25-(OH)-D3、Sfrp-5和Nesfatin 1的表达水平与GDM发病的相关性分析[J]. 河北医药, 2021, 43 (9 ): 1347-1349, 1353. 10.3969/j.issn.1002-7386.2021.09.014. 34966159
ZHANG Wenrong , WANG Sujian , SHI Jianlei , The correlation between the expression of 25-(OH)-D3, Sfrp-5, Nesfatin 1 and the pathogenesis of GMD[J]. Hebei Medical Journal, 2021, 43 (9 ): 1347-1349, 1353. 10.3969/j.issn.1002-7386.2021.09.014.
42 Fan ZW , Dong JJ , Mu YD , Nesfatin-1 protects against diabetic cardiomyopathy in the streptozotocin-induced diabetic mouse model via the p38-MAPK pathway[J]. Bioengineered, 2022, 13 (6 ): 14670-14681. 10.1080/21655979.2022.2066748. 35818327
43 Ayada C , Toru Ü , Korkut Y . Nesfatin-1 and its effects on different systems[J]. Hippokratia, 2015, 19 (1 ): 4-10. 26435639
44 Ravussin A , Youm YH , Sander J , Loss of nucleobindin-2 causes insulin resistance in obesity without impacting satiety or adiposity[J]. Cell Rep, 2018, 24 (5 ): 1085-1092.e6. 10.1016/j.celrep.2018.06.112. 30067966
45 Yang ML , Zhang ZH , Wang C , Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance[J]. Diabetes, 2012, 61 (8 ): 1959-1968. 10.2337/db11-1755. 22688332
46 Wu DD , Yang ML , Chen Y , Hypothalamic nesfatin-1/NUCB2 knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3 signaling pathway in rats[J]. Diabetes, 2014, 63 (4 ): 1234-1247. 10.2337/db13-0899. 24478398
47 Bray GA . Obesity, a disorder of nutrient partitioning: the MONA LISA hypothesis[J]. J Nutr, 1991, 121 (8 ): 1146-1162. 10.1093/jn/121.8.1146. 1861165
48 Lim J , Park HS , Kim J , Depot-specific UCP1 expression in human white adipose tissue and its association with obesity-related markers[J]. Int J Obes, 2020, 44 (3 ): 697-706. 10.1038/s41366-020-0528-4.
