Are Inflamed Periodontal Tissues Endogenous Source of Advanced Glycation End-Products (AGEs) in Individuals with and without Diabetes Mellitus? A Systematic Review

Abstract

Advanced glycation end-products (AGEs) are heterogeneous compounds formed when excess sugars condense with the amino groups of nucleic acids and proteins. Increased AGEs are associated with insulin resistance and poor glycemic control. Recently, inflamed periodontal tissues and certain oral bacteria were observed to increase the local and systemic AGE levels in both normoglycemic and hyperglycemic individuals. Although hyperglycemia induced AGE and its effect on the periodontal tissues is known, periodontitis as an endogenous source of AGE formation is not well explored. Hence, this systematic review is aimed to explore, for the first time, whether inflamed periodontal tissues and periodontal pathogens have the capacity to modulate AGE levels in individuals with or without T2DM and how this affects the glycemic load. Six electronic databases were searched using the following keywords: (Periodontitis OR Periodontal disease OR Periodontal Inflammation) AND (Diabetes mellitus OR Hyperglycemia OR Insulin resistance) AND Advanced glycation end products. The results yielded 1140 articles, of which 13 articles were included for the review. The results showed that the mean AGE levels in gingival crevicular fluid was higher in individuals with diabetes mellitus and periodontitis (521.9 pg/mL) compared to healthy individuals with periodontitis (234.84 pg/mL). The serum AGE levels in normoglycemic subjects having periodontitis was higher compared to those without periodontitis (15.91 ng/mL vs. 6.60 ng/mL). Tannerella forsythia, a common gram-negative anaerobe periodontal pathogen in the oral biofilm, was observed to produce methylglyoxal (precursor of AGE) in the gingival tissues. Increased AGE deposition and activate of AGE receptors was noted in the presence of periodontitis in both normoglycemic and hyperglycemic individuals. Hence, it can be concluded that periodontitis can modulate the local and systemic levels of AGE levels even in absence of hyperglycemia. This explains the bidirectional relationship between periodontitis and development of prediabetes, incident diabetes, poor glycemic control, and insulin resistance.

Comparing the activity level of salivary matrix metalloproteinase‐8 in patients with diabetes and moderate to severe chronic generalized periodontitis

“…Inflammatory mediators produced locally in periodontitis enter the systemic bloodstream and can cause insulin resistance. On the other hand, in diabetic people, the end products of glycosylation react with special receptors in the gingival cells and cause the production of the final inflammatory protein (Cecoro et al, 2020 ; Chopra et al, 2022 ; Wang et al, 2022 ). These markers are produced locally, then enter the person's circulatory system and induce or sustain a systemic inflammatory state that can lead to insulin resistance in cells and poor blood sugar control (Preshaw & Bissett, 2019 ).…”

Resveratrol attenuates advanced glycation end product-induced senescence and inflammation in human gingival fibroblasts

“…These effects can ultimately result in periodontitis. 6 In addition, high concentrations of AGEs in serum, gingival tissue and gingival crevicular fluid were also found more commonly in type 2 diabetic patients with periodontitis. 7 , 8 , 9 …”

Risk factors of severe periodontitis in kidney transplant recipients: A case‐control study

“…AGE represent heterogeneous compounds formed in the process of glycation of host proteins, amino groups of nucleic acids, and lipids. Increased aggregation of AGE in tissues leads to impaired formation of extracellular matrix, which affects physiological and mechanical functions and is associated with increased inflammation of periodontal tissues 23 . Higher levels of AGE are associated with ESRD, 24 DM, 24,25 high body mass index, 26 and cardiovascular (CV) events 27 …”

“…Increased aggregation of AGE in tissues leads to impaired formation of extracellular matrix, which affects physiological and mechanical functions and is associated with increased inflammation of periodontal tissues. 23 Higher levels of AGE are associated with ESRD, 24 DM, 24,25 high body mass index, 26 and cardiovascular (CV) events. 27 KTRs undergo immunosuppressive therapy and are at higher risk of developing opportunistic infections, including periodontitis.…”