Serum Advanced Glycation End Products as Drivers of Poor Tendon Outcomes in Diabetes? An Emerging Hypothesis and Narrative Review

INTRODUCTION: Tendon injuries in individuals with diabetes are difficult to reverse, and the mechanisms driving poor healing, extracellular matrix disruption, and altered biomechanics remain poorly understood. Many individuals with prediabetes or diabetes are also overweight or obese, and increased visceral adiposity alters adipokine levels and promotes chronic inflammation. While multiple factors influence tendon healing and extracellular matrix (ECM) remodelling, we suggest that circulating advanced glycation end-products (AGEs) may drive delayed healing, collagen disorganization, and compromised biomechanical properties in diabetes. METHODS: A comprehensive narrative review of the literature was conducted using PubMed and Embase to synthesize current and emerging evidence on the relationship between AGEs, tendon properties, and tendon healing in diabetes. Experimental, translational, and clinical studies, as well as relevant review articles involving cell, animal, and human models, were critically analysed. RESULTS: This narrative review explores the limited evidence linking serum AGE accumulation and Receptor for Advanced Glycation End-Product (RAGE) activation to tendon pathology and poor healing. Traditionally, tendon dysfunction in diabetes has been attributed to non-enzymatic collagen crosslinking. However, there is mixed evidence demonstrating increased tendon AGE content or stiffness in diabetic patients compared to age-matched controls, suggesting alternative mechanisms. Therefore, we outline recent in vitro, animal, and human studies on AGE and RAGE in tendons and propose future directions. CONCLUSION: We propose that a systemic rise in serum AGEs impairs tendon healing by activating RAGE and disrupting cellular pathways required for repair. Future studies investigating the role of AGEs and other circulating factors may provide insights into the high incidence of tendon injuries and impaired healing in individuals with diabetes and related metabolic disorders.