Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis of Type 2 Diabetes
Joseph L. Evans, Ira D. Goldfine, Betty A. Maddux and Gerold M. Grodsky





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-B, 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-B, 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, -lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.

I. Introduction

II. Overview of the Development of Type 2 Diabetes

III. Oxidative Stress and Complications of Diabetes
A. Hyperglycemia leads to mitochondrial dysfunction and activation of stress pathways both in vitro and in vivo
B. ROS generation and oxidative stress
C. NF-B: a primary target for activation by hyperglycemia, ROS, oxidative stress, and inflammatory cytokines
D. Hyperglycemia-dependent NF-B activation in patients with diabetes mellitus
E. Decreased levels of antioxidants in diabetes and prevention of NF-B activation by antioxidants
F. VEGF: an initiator of diabetic complications?
G. Antioxidants inhibit VEGF production
H. JNK/SAPK and p38 MAPK pathways: other primary targets for activation by hyperglycemia, ROS, and inflammatory cytokines
I. Additional important hyperglycemia-activated pathways
J. ROS generation by enzymatic pathways of arachidonic/linoleic acid metabolism

IV. Oxidative Stress and Insulin Resistance
A. Activation of stress-kinases, IRS phosphorylation, and insulin resistance
B. IKKß, IRS proteins, and insulin resistance
C. Oxidative stress, protein tyrosine phosphatases, and insulin resistance
D. Obesity, fatty acids, and insulin resistance
E. Fatty acids and insulin resistance
F. Fatty acids, redox balance, and activation of stress pathways

V. Oxidative Stress and ß-Cell Dysfunction
A. ß-Cell glucose-induced toxicity
B. ß-Cell lipid-induced toxicity
C. ß-Cell combined glucose/lipid toxicity
D. Role of oxidative stress in ß-cell dysfunction
VI. Conclusions and Implications

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