In both type 1 and type 2 diabetes, diabetic complications in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addition to their ability to directly inflict damage on macromolecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress-sensitive pathways. These pathways include nuclear factor-κB, p38 mitogen-activated protein kinase, NH2-terminal Jun kinases/stress-activated protein kinases, hexosamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same pathways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, we propose here that the hyperglycemia-induced, and possibly FFA-induced, activation of stress pathways plays a key role in the development of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes.
Address correspondence and reprint requests to Dr. Joseph L. Evans, Medical Research Institute, 444 De Haro St., Suite 209, San Francisco, CA 94107-2347. E-mail:.
Received for publication 8 January 2002 and accepted in revised form 15 April 2002.
J.L.E. has received consulting fees from Medical Research Institute.
AGE, advanced glycation end product; ERK, extracellular signal−related kinases; FFA, free fatty acid; IκB, inhibitory protein κB; IKK-β, IκB kinase-β; IR, insulin receptor; IRS, IR substrate; JNK, NH2-terminal Jun kinase; LA, α-lipoic acid; NF-κB, nuclear factor-κB; MAP, mitogen-activated protein; MAPK, MAP kinase; NAC, N-acetyl-l-cysteine; PKC, protein kinase C; RAGE, receptor for AGEs; RNS, reactive nitrogen species; ROS, reactive oxygen species; SAPK, stress-activated protein kinases; VEGF, vascular endothelial growth factor.