Hyperglycemia and the pathobiology of diabetic complications.
Both type I and type II diabetes are powerful and independent risk factors for coronary artery disease (CAD), stroke, and peripheral arterial disease. Atherosclerosis accounts for virtually 80% of all deaths among diabetic patients. Prolonged exposure to hyperglycemia is now recognized as a major factor in the pathogenesis of diabetic complications, including atherosclerosis. Hyperglycemia induces a large number of alterations at the cellular level of vascular tissue that potentially accelerates the atherosclerotic process. Animal and human studies have elucidated several major mechanisms that encompass most of the pathological alterations observed in the diabetic vasculture. These include: (1) Nonenzymatic glycosylation of proteins and lipids which can interfere with their normal function by disrupting molecular conformation, alter enzymatic activity, reduce degradative capacity, and interfere with receptor recognition. In addition, glycosylated proteins interact with a specific receptor present on all cells relevant to the atherosclerotic process, including monocyte-derived macrophages, endothelial cells, and smooth muscle cells. The interaction of glycosylated proteins with their receptor results in the induction of oxidative stress and proinflammatory responses. (2) Protein kinase C (PKC) activation with subsequent alteration in growth factor expression. (3) Shunting of excess intracellular glucose into the hexosamine pathway leads to O-linked glycosylation of various enzymes with perturbations in normal enzyme function. (4) Hyperglycemia increases oxidative stress through several pathways. A major mechanism appears to be the overproduction of the superoxide anion (O-2 ) by the mitochondrial electron transport chain. (5) Hyperglycemia promotes inflammation through the induction of cytokine secretion by several cell types including monocytes and adipocytes. Importantly, there appears to be a tight pathogenic link between hyperglycemia-induced oxidant stress and other hyperglycemia-dependent mechanisms of vascular damage described above, namely AGEs formation, PKC activation, and increased flux through the hexosamine pathway. For example, hyperglycemia-induced oxidative stress promotes both the formation of advanced glycosylation end products and PKC activation.
Aronson
Doron
D
Department of Cardiology, Rambam Medical Center, Haifa, Israel.
D003327:Coronary Disease / Q000453:epidemiology* / Q000503:physiopathology; D048909:Diabetes Complications / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003925:Diabetic Angiopathies / Q000453:epidemiology* / Q000503:physiopathology; D004789:Enzyme Activation; D017127:Glycation End Products, Advanced / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011493:Protein Kinase C