Journal List > J Korean Endocr Soc > v.21(6) > 1003327

J Korean Endocr Soc. 2006 Dec;21(6):448-459. Korean.
Published online December 20, 2006.
Copyright © 2006 Korean Endocrine Society
Mechanism of Developing Diabetic Vascular Complication by Oxidative Stress
Bo Hyun Kim and Seok Man Son
Department of Internal Medicine, Pusan National University School of Medicine, Korea.

Macrovascular and microvascular diseases are currently the principal causes of morbidity and mortality in the patients with diabetes mellitus. Oxidative stress has been postulated to be a major contributor to the pathogenesis of these events. There is considerable evidence that many biochemical pathways that are adversely affected by hyperglycemia are associated with the generation of reactive oxygen species, and this ultimately leads to increased oxidative stress in a variety of tissues. In the absence of appropriate compensation by the endogenous antioxidant defense network, increased oxidative stress leads to the activation of stress-sensitive intracellular signaling pathways and the formation of gene products that cause cellular damage and contribute to the late complications of diabetes. Hyperglycemia increases oxidant production by multiple pathways rather than by a single dominant pathway. Glucose can undergo nonenzymatic reactions to form gluco-oxidants and glycated products, which can be oxidants. Metabolism of excessive intracellular glucose can occur by several processes such as aldose reductase, mitochondrial oxidative phosphorylation, activation of NAD(P)H oxidases, and the alteration of the NADPH/NADP ratios. Reactive oxygen species participate in vascular smooth muscle cell growth and migration, modulation of endothelial function, including abnormal endothelium-dependent relaxation and the expression of a proinflammatory phenotype, and modification of the extracellular matrix. All of these events contribute to the development of diabetic microvascular and macrovascular complications, suggesting that the sources of reactive oxygen species and the signaling pathways that they modify may represent important therapeutic targets.

Keywords: Diabetic complication; Diabetes; NADPH/NADP; Oxidative stress


Fig. 1
Overview of the sources of ROS in diabetes and their links to atherosclerosis. oxLDL, oxidized LDL; FFA, free fatty acid; AGEs, advanced glycation end-products; VSMC, vascular smooth muscle cells; ROS, reactive oxygen species.
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Fig. 2
The generation and removal pathways of ROS in human body.
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Fig. 3
Consequences of oxidative stress-induced signaling mechanisms in diabetes. ROS, reactive oxygen species; NO, nitric oxide; O2-, superoxide; eNOS, endothelial nitric oxide synthase; NF-κB, nuclear factor-κB; FFA, free fatty acids; AGEs, advanced glycation end-products; RAGE, receptor for AGE; PDGF, platelet-derived growth factor; PDGR-R, PDGF receptor; ADMA, asymmetric dimethyl arginine; DDAH, dimethylarginine dimethylaminohydrolase; PKC, protein kinase C; PLA2, phospholipase A2 BH4, tetrahydrobiopterin; GTPCH, GTP-cyclohydrolase I; MMP-9, matrix metalloproteinase-9; p38MAPK, p38 mitogen-activated kinase; IL-8, interleukin-8; oxLDL, oxidized LDL; LOX-1, lectin-like oxLDL receptor; MCP-1, monocyte chemoattractant protein-1; VCAM-1, vascular cellular adhesion molecule-1; TNFα, tumor necrosis factor-α.
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Fig. 4
The suggested mechanisms of development of oxidative stress-induced vascular complications in diabetes and hypertension. XO, xanthine oxidase; O2-, superoxide; eNOS, endothelial nitric oxide synthase; ox-LDL, oxidized LDL; MPO, myeloperoxidase; HOCl, hydroxyl chloride; VEGF, vascular endothelial growth factor; TNF-α, tumor necrosis factor-α; Ang II, angiotensin II.
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