Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes

JL Evans, ID Goldfine, BA Maddux… - Endocrine …, 2002 - academic.oup.com
JL Evans, ID Goldfine, BA Maddux, GM Grodsky
Endocrine reviews, 2002academic.oup.com
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-κB, 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 …
Abstract
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-κB, 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-κB, 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, α-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.
Oxford University Press