A rational approach to pathogenesis and treatment of type 2 diabetes mellitus, insulin resistance, inflammation, and atherosclerosis

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Abstract

Type 2 diabetes and obesity are major risk factors for the development of coronary artery disease (CAD) and premature atherosclerosis. Both conditions are associated with insulin resistance, oxidative stress, and inflammation. Inflammatory mediators, including plasma interleukin 6, tumor necrosis factor α, and tumor necrosis factor R are elevated in these individuals. The elevations of inflammatory mediators may contribute to the pathogenesis of atherosclerosis, because atherosclerosis is an inflammation of the arterial wall. There is evidence that the thiazolidinedione (TZD) class of drugs may alleviate some of the adverse atherosclerotic effects common in patients with type 2 diabetes. Considerable recent data suggest that the TZDs possess anti-inflammatory properties and exert an effect on the atherogenic process, including effects on endothelial function, monocyte/macrophage function, lipid abnormalities, smooth muscle cell migration, and fibrinolysis, all functions that are abnormal in the presence of insulin resistance. These actions of TZDs are consistent with the recently described anti-inflammatory effects of insulin. The use of TZDs as potent anti-inflammatory agents in patients with type 2 diabetes is an approach that would normalize glucose levels, as well as potentially alleviate the long-term risk of atherosclerosis.

Section snippets

Process of atherogenesis

Recent observations have focused attention on additional mechanisms that may be relevant to atherogenesis both in patients with type 2 diabetes and in the obese. Patients with type 2 diabetes and/or obesity have an increase in oxidative stress and inflammation. Increased oxidative stress in type 2 diabetes is indicated by an increase in reactive oxygen species (ROS) generation by circulating mononuclear cells,10 increased lipid peroxidation,11 protein carbonylation,12 nitro-tyrosine formation,13

Vascular reactivity

Vascular reactivity is, by definition, the response of a blood vessel to a challenge or stimulus. Thus, blood vessels will respond variously to anoxia, ischemia, hypercapnia, thermal challenge, and exercise. The most convenient method currently used is to measure dilation of the brachial artery after a period of forearm ischemia.47, 48 Because the dilation is endothelium dependent and flow mediated, it is subnormal in conditions associated with endothelial dysfunction, including diabetes. Thus,

Anti-inflammatory effect of thiazolidinediones

TZDs are insulin sensitizers that exert their action through binding to peroxisome proliferator–activated receptor γ receptors. Binding of the TZD to peroxisome proliferator–activated receptor γ receptors leads to their heterodimerization with retinoid receptor, activation binding to gene promoters, and gene transcription.54, 55 Initially, it was believed that the genes regulated by these drugs were related to carbohydrate and lipid metabolism. These actions putatively accounted for their

Anti-inflammatory effect of insulin

The available data with TZDs prompted a series of experiments with insulin to test the hypothesis that if insulin sensitizers are anti-inflammatory, insulin is also anti-inflammatory. In vitro data obtained from human aortic endothelial cells showed that insulin suppressed intracellular adhesion molecule 1 expression and secretion and that this effect was nitric oxide mediated.75 Insulin is known to induce nitric oxide release and to enhance nitric oxide synthase expression in endothelial cells.

Conclusions

Insulin is an anti-inflammatory hormone, and an insulin-resistant state is proinflammatory and potentially proatherogenic, as well as being associated with hyperglycemia and diabetes when there is a concomitant defect in insulin secretion. TZDs are potent anti-inflammatory drugs that are more appropriately used to treat the state of insulin resistance, which is proinflammatory. This approach would induce both a normalization of glucose homeostasis and potentially reduce the long-term risk of

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