Breakers of advanced glycation end products restore large artery properties in experimental diabetes

TLDR

Glucose and other reducing sugars nonenzymatically glycate proteins, forming advanced glycation end products (AGEs) that increase collagen crosslinking and arterial stiffness, especially in diabetes. The study aimed to develop a new class of AGE crosslink breakers that could react with and cleave covalent AGE-derived protein crosslinks. These breakers act by cleaving the covalent crosslinks that accumulate in connective tissue. Treatment of streptozotocin‑induced diabetic rats with ALT‑711 for 1–3 weeks reversed the diabetes‑induced increase in large artery stiffness, improving systemic arterial compliance, aortic impedance, carotid compliance and distensibility, with implications for treating diabetes‑related complications and aging.

Abstract

Glucose and other reducing sugars react with proteins by a nonenzymatic, posttranslational modification process called nonenzymatic glycation. The formation of advanced glycation end products (AGEs) on connective tissue and matrix components accounts largely for the increase in collagen crosslinking that accompanies normal aging and which occurs at an accelerated rate in diabetes, leading to an increase in arterial stiffness. A new class of AGE crosslink "breakers" reacts with and cleaves these covalent, AGE-derived protein crosslinks. Treatment of rats with streptozotocin-induced diabetes with the AGE-breaker ALT-711 for 1-3 weeks reversed the diabetes-induced increase of large artery stiffness as measured by systemic arterial compliance, aortic impedance, and carotid artery compliance and distensibility. These findings will have considerable implications for the treatment of patients with diabetes-related complications and aging.