Diabetic Vascular Complications: Pathophysiology, Biochemical Basis and Potential Therapeutic Strategy

Abstract

Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Recent large prospective clinical studies have shown that intensive glucose control reduces effectively microvascular complications among patients with diabetes, and insulin resistance and postprandial hyperglycemia seem to be involved in diabetic macrovascular complications. Chronic hyperglycemia is a major initiator of diabetic vascular complications. Indeed, high glucose, via various mechanisms such as increased production of advanced glycation end products, activation of protein kinase C, stimulation of the polyol pathway and enhanced reactive oxygen species generation, regulates vascular inflammation, altered gene expression of growth factors and cytokines, and platelet and macrophage activation, thus playing a central role in the development and progression of diabetic vascular complications. This article summarizes the molecular mechanisms of diabetic vascular complications and the potential therapeutic interventions that may prevent these disorders even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.

Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation

“…RAGE is a signal-transducing receptor for AGE [1]. Therefore, we first examined the effect of telmisartan on RAGE expression in Hep3B cells.…”

“…Non-enzymatic modification of proteins by reducing sugars, a process that is also known as the Maillard reaction, progresses at an extremely accelerated rate in diabetes, thus leading to the formation of AGE [1]. Recent understanding of this process has revealed that the receptor system for AGE (RAGE) plays a central role in the pathogenesis of diabetic vascular complications such as cardiovascular disease [1].…”

“…Recent understanding of this process has revealed that the receptor system for AGE (RAGE) plays a central role in the pathogenesis of diabetic vascular complications such as cardiovascular disease [1].…”

“…However, the molecular mechanism for the elevation of CRP in diabetes is not fully understood. Since crosstalk between the AGE-RAGE system and angiotensin II (Ang II) has been proposed in the pathogenesis of accelerated atherosclerosis in diabetes [1], we examined here whether and how telmisartan, a unique Ang II type 1 receptor blocker (ARB) with peroxisome proliferator-activated receptor-γ (PPAR-γ)-modulating activity [4], could inhibit AGE-induced CRP production in a human hepatoma cell line, Hep3B cells.…”

DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice

“…6,7 There is accumulating evidence that interaction of AGE with the receptor for AGE (RAGE) contributes to the development and progression of various age-or diabetes-related disorders, including cardiovascular disease, Alzheimer's disease, osteoporosis, cancer growth and metastasis. [8][9][10][11] Indeed, we, along with others, have previously shown that AGE stimulate growth or migration of pancreatic cancer, lung cancer, malignant melanoma and renal cell carcinoma cells in vitro through the interaction with RAGE. [12][13][14][15] Therefore, the AGE-RAGE axis may be a therapeutic target for slowing the progression of cancers in patients with diabetes.…”