
==== Front
World J Diabetes
WJD
World Journal of Diabetes
1948-9358
Baishideng Publishing Group Inc

jWJD.v15.i9.pg1842
10.4239/wjd.v15.i9.1842
94930
Editorial
Link between periodontitis and diabetic retinopathy: Inflammatory pathways and clinical implications
Zhao Y et al. Periodontitis, diabetic retinopathy and inflammation
Zhao Yu Geriatric Medicine Center, Department of Endocrinology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China

Shen Quan-Quan Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, China
Department of Nephrology, Zhejiang Provincial People’s Hospital Bijie Hospital, Bijie 551700, Guizhou Province, China. spring198457@sina.com

Author contributions: Zhao Y drafted the manuscript; Shen QQ designed the research and revised the manuscript; both authors have read and approved the final manuscript.

Supported by the Zhejiang Medical Technology Project, No. 2022RC009 ; and National Natural Science Foundation of China, No. 81900692 .

Corresponding author: Quan-Quan Shen, MD, Associate Professor, Doctor, Urology and Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), No. 158 Shangtang Road, Hangzhou 310014, Zhejiang Province, China; Department of Nephrology, Zhejiang Provincial People’s Hospital Bijie Hospital, No. 112 Guanghui Road, Bijie 551700, Guizhou Province, China. spring198457@sina.com

15 9 2024
15 9 2024
15 9 18421846
28 3 2024
13 6 2024
19 6 2024
©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
The bidirectional relationship between periodontitis and type 2 diabetes mellitus has been well-established. However, the underlying molecular mechanisms remain unclear. Diabetic retinopathy (DR) is an important complication of diabetes, but there are few studies on the relationship between DR and periodontitis, especially on the intrinsic inflammatory pathway mechanism. This article reviews the latest clinical data on how diabetes promotes susceptibility to periodontitis from the epidemiological and molecular perspectives, with a special focus on the key roles of systemic inflammation and endothelial dysfunction in the interplay between DR and periodontitis. Comprehension of the intertwined pathogenesis of DR and periodontitis can better guide the development of comprehensive management strategies for glycemic control and periodontal health, with the aim of mitigating the progression of DR and enhancing overall well-being.

Type 2 diabetes mellitus
Diabetic retinopathy
Microvascular complications
Periodontitis
Systemic inflammation
Endothelial dysfunction
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pmc Core Tip: This editorial elucidates the significant link between periodontitis and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus. By examining the inflammatory pathways shared by both conditions, we highlight how periodontal inflammation not only exacerbates systemic inflammation but also contributes to vascular complications typical of DR. The study underscores the clinical implications of incorporating periodontal care into the management of diabetes, and advocates integrated treatment approaches to enhance patient outcomes.

INTRODUCTION

Diabetes mellitus (DM) is a challenging chronic disease that affects millions worldwide, leading to complications such as microvascular damage and diabetic retinopathy (DR), a primary cause of blindness[1,2]. Periodontitis is present in approximately 45%-50% of adults, with the prevalence rising to over 60% in those aged 65 years and above[3]. Severe periodontitis is the sixth most common disease of 291 assessed globally[4]. A well-recognized link exists between prolonged hyperglycemia and increased periodontal destruction[5], and severe periodontitis significantly exacerbates the complications of diabetes[6,7]; however, the exact molecular mechanisms remain unclear[8]. Recently, this journal published an article exploring the potential links between DR and periodontitis, entitled “Correlation of Periodontal Inflamed Surface Area with Glycated Hemoglobin, Interleukin-6, and Lipoprotein (a) in Type 2 Diabetes with Retinopathy”. The present study intends to build on that article, reviewing the latest clinical data on diabetes susceptibility and periodontitis, discussing potential molecular mechanisms with a special focus on new data related to inflammatory factors, to better understand the intertwined pathogenesis of diabetes and periodontitis, and to improve the management of these conditions.

CORRELATION BETWEEN PERIODONTAL DISEASE AND DR

Periodontitis, a chronic inflammatory non-communicable disease, is characterized by the destruction of periodontal tissues, including the alveolar bone, the presence of periodontal pockets, and probing bleeding[3]. The accumulation of microbial biofilm at and below the gum margin triggers it, activating the host’s immune-inflammatory response and resulting in the continuous production of inflammatory mediators[9,10]. Periodontitis has increasingly been recognized as a potential contributing factor to the incidence and progression of various systemic diseases[11]. Epidemiological and experimental studies suggest that periodontitis can influence overall health through multiple molecular mechanisms, being independently associated with the prevalence and prognosis of prediabetes, type 2 DM (T2DM), cardiovascular diseases, and cognitive impairments[12-15].

Mechanisms through which periodontitis negatively impacts T2DM include bacteremia, vascular inflammation, systemic oxidative stress affecting β-cell function, and systemic inflammation, leading to an increased onset of diabetic complications[10,16,17]. It has been discovered through clinical research that alleviating periodontitis can improve glycemic control in patients with diabetes[18]. Hemoglobin A1c (HbA1c) reflects the average blood glucose levels over the past 2-3 months and is a crucial indicator for assessing glycemic control in patients with diabetes. It is strongly associated with the risk of diabetes complications[19]. Moreover, findings from a large observational study indicate that a 1-point (1%) decrease in HbA1c is associated with a significant reduction in the risk of various complications: 12% for stroke, 21% for diabetes-related deaths, 14% for myocardial infarction, 19% for cataract extraction, and 43% for amputation[20]. A Cochrane review of 35 studies involving 3249 participants found that periodontal treatment could reduce HbA1c levels in T2DM patients by approximately 0.3% at 6 months and by about 0.5% at 12 months[21]. In a randomized controlled trial involving patients with T2DM, non-surgical periodontal treatment resulted in a 0.9% reduction in HbA1c levels and decreased the levels of serum inflammatory biomarkers, such as interleukins (IL) and granulocyte colony-stimulating factor[22]. Moreover, successful periodontal treatment has been shown to improve clinical local and systemic inflammatory biomarkers, even in patients with poor glycemic control[2,23].

Conversely, it is also understood that diabetes is a risk factor for periodontitis. Previous studies have demonstrated that individuals with diabetes are more susceptible to periodontal disease and have faster progression of periodontitis compared to non-diabetics[7,18,24-26]. Effective glycemic control, even without periodontal treatment, can improve probing bleeding in patients. Additionally, patients with well-managed diabetes have shown a significant reduction in the progression of periodontal disease over 5 years[27]. The mechanisms leading to poor periodontal outcomes in patients with diabetes and hyperglycemia include excessive systemic inflammation, reduced neutrophil functional efficiency, imbalanced T-helper cell responses, and inhibition of periodontal wound healing due to the formation of advanced glycation end-products (AGEs)[28].

DR, as a microvascular complication of diabetes, leads to significant visual impairment and blindness among the diabetic population. Research indicates that T2DM patients with periodontitis have an increased risk of developing DR compared to those without periodontitis[29]. Furthermore, a positive correlation exists between the severity of DR and the severity of periodontitis[24,30]. Given the established link between periodontitis and DR, it is critical to determine the underlying mechanisms connecting these two conditions.

The interconnection between DR and periodontitis underscores a complex interplay of pathophysiological mechanisms primarily mediated through systemic inflammation and endothelial dysfunction. Both conditions share a commonality in their pathogenesis, rooted in the systemic inflammatory response and oxidative stress, which serve as pivotal links in their association. In the context of diabetes, hyperglycemia-induced oxidative stress, and the formation of AGEs play a critical role in endothelial dysfunction, a hallmark of microvascular complications including DR[31]. Endothelial dysfunction facilitates a pro-inflammatory state, exacerbating the vascular damage seen in DR[32].

Similarly, periodontitis, characterized by persistent oral infection and inflammation, contributes to the systemic inflammatory burden through the dissemination of pro-inflammatory cytokines such as tumor necrosis factor-alpha, IL-6, and C-reactive protein into the systemic circulation[10,16,33]. These inflammatory mediators can further impair endothelial function, thus potentially exacerbating the microvascular complications of diabetes[34]. Moreover, under the influence of inflammation, periodontitis can also lead to dyslipidemia, atherosclerosis, and aggravation of retinal hypoxia, leading to neovascularization and promoting the progression of DR[30].

Furthermore, the increased systemic inflammatory response in patients with periodontitis may exacerbate insulin resistance, a key feature of T2DM, thereby worsening glycemic control. Poor glycemic control, in turn, can accelerate the progression of DR through mechanisms such as increased oxidative stress, upregulation of inflammatory pathways, and vascular endothelial growth factor production, which promotes neovascularization and the progression of DR[34,35].

Although the proposed mechanisms offer plausible explanations, the current evidence base underpinning the association between DR and periodontitis is deemed to be of low quality[36]. Direct verification of these mechanisms is also lacking, signifying the necessity for augmented research efforts. There is a critical need for future studies characterized by larger sample sizes, enhanced models for adjusting confounders, and the adoption of prospective analyses to elucidate the relationship between these conditions more clearly.

HIGHLIGHTS OF THE CITED ARTICLE

In recent years, the intricate interplay between periodontitis and DR among individuals with T2DM has garnered significant attention within the medical and dental research communities. The observational study conducted by Thazhe Poyil et al[37], embarked on a comprehensive exploration of this nexus, specifically examining the correlation between the periodontal inflamed surface area (PISA) and HbA1c, IL-6, and lipoprotein(a) [Lp(a)] in T2DM subjects with and without DR. Through a cross-sectional design, involving 80 T2DM subjects, the research team meticulously assessed periodontal and systemic parameters, thereby providing a robust dataset for analysis.

The findings revealed a significantly higher proportion of periodontitis, severity of periodontitis, clinical attachment loss (CAL), PISA, IL-6, and Lp(a) in T2DM subjects with DR compared to those without DR, underscoring a pronounced inflammatory burden in subjects with concomitant DR. Notably, HbA1c exhibited a positive correlation with CAL and PISA, highlighting the intricate link between glycemic control, periodontal inflammation, and diabetic complications.

The study’s implications are manifold. Firstly, it underscores the necessity of integrating periodontal care into the diabetes management paradigm, suggesting that mitigating periodontal inflammation could play a role in staving off DR progression. Furthermore, it calls for a heightened awareness among healthcare providers regarding the bidirectional relationship between periodontitis and diabetes complications, advocating for a multidisciplinary approach to patient care. Secondly, the research highlights the potential of PISA as a valuable tool in assessing the systemic impact of periodontal disease, advocating its broader adoption in clinical settings. Thirdly, the study sets a precedent for future research to explore targeted interventions aimed at reducing periodontal inflammation as a strategy to improve overall outcomes in T2DM patients, particularly those at risk of or suffering from DR. Lastly, given the scarcity of research on the specific roles of IL-6 and Lp(a) in the interplay between periodontitis and DR, this study fills an important gap. It contributes to a deeper understanding of the underlying mechanisms, which could pave the way for novel therapeutic targets.

This manuscript is not without limitations. Firstly, the study is limited by a relatively small sample size and a failure to control for some key confounding factors related to periodontitis and DR, leading to insufficient evidence. Secondly, the cross-sectional design complicates the elucidation of potential mechanisms linking periodontitis with diabetes-associated microvascular complications, underscoring the need for further prospective and mechanistic research to clarify the associations or causal relationships.

CONCLUSION

The potential pathophysiological mechanisms linking periodontitis and DR involve a complex interplay of systemic inflammation, endothelial dysfunction, oxidative stress, and exacerbated insulin resistance. This bidirectional relationship underscores the need for comprehensive management strategies in diabetic patients, targeting both glycemic control and periodontal health, to mitigate the progression of DR and improve overall vascular health. Further investigation into the specific inflammatory markers and cytokines involved in both diseases could illuminate potential therapeutic targets.

Conflict-of-interest statement: The authors have no financial relationships to disclose.

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Medicine, general and internal

Country of origin: China

Peer-review report’s classification

Scientific Quality: Grade B, Grade B

Novelty: Grade B, Grade B

Creativity or Innovation: Grade B, Grade B

Scientific Significance: Grade B, Grade B

P-Reviewer: Roomi AB S-Editor: Chen YL L-Editor: A P-Editor: Zhao YQ
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