Mechanisms linking diabetes mellitus to the development of atherosclerosis: a role for endoplasmic reticulum stress and glycogen synthase kinase-3.

Recent decades have seen a significant increase in the incidence of diabetes mellitus. The number of individuals with diabetes is projected to reach 300 million by the year 2025. Diabetes is a leading cause of blindness, renal failure, lower limb amputation, and an independent risk factor for atherosclerotic cardiovascular disease (CVD)--a leading cause of death in Western society. Understanding the molecular and cellular mechanisms by which diabetes mellitus promotes atherosclerosis is essential to developing methods to treat and prevent diabetes-associated CVD. This review summarizes our current knowledge of the mechanisms by which diabetes may promote atherogenesis and specifically focuses on a novel pathway linking these 2 conditions. We hypothesize that the accumulation of intracellular glucosamine observed in conditions of chronic hyperglycaemia may promote atherogenesis via a mechanism involving dysregulated protein folding, activation of endoplasmic reticulum (ER) stress, and increased glycogen synthase kinase (GSK)-3 activity. The identification of this novel mechanism provides a promising hypothesis and multiple new targets for potential therapeutic intervention in the treatment of diabetes mellitus and accelerated atherosclerosis.