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.
Robertson
Lindsie A
LA
Department of Biochemistry, McMaster University, Hamilton, ON, Canada.
Kim
Anna J
AJ
Werstuck
Geoff H
GH
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D048909:Diabetes Complications / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3