Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes.
In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.
Evans
Joseph L
JL
University of California at San Francisco, San Francisco, California 94143, USA. jevansphd@earthlink.net
Goldfine
Ira D
ID
Maddux
Betty A
BA
Grodsky
Gerold M
GM
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology; D016228:Endothelial Growth Factors / Q000502:physiology; D006801:Humans; D006943:Hyperglycemia / Q000150:complications; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007515:Islets of Langerhans / Q000503:physiopathology; D008222:Lymphokines / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000975:Antioxidants; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020928:Mitogen-Activated Protein Kinases