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Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes

Abstract

Endothelial dysfunction is one manifestation of the many changes induced in the arterial wall by the metabolic abnormalities accompanying diabetes and insulin resistance. In type 1 diabetes, endothelial dysfunction is most consistently found in advanced stages of the disease. In other patients, it is associated with nondiabetic insulin resistance and probably precedes type 2 diabetes. In obesity and insulin resistance, increased secretion of proinflammatory cytokines and decreased secretion of adiponectin from adipose tissue, increased circulating levels of free fatty acids, and postprandial hyperglycemia can all alter gene expression and cell signaling in vascular endothelium, cause vascular insulin resistance, and change the release of endothelium-derived factors. In diabetes, sustained hyperglycemia causes increased intracellular concentrations of glucose metabolites in endothelial cells. These changes cause mitochondrial dysfunction, increased oxidative stress, and activation of protein kinase C. Dysfunctional endothelium displays activation of vascular NADPH oxidase, uncoupling of endothelial nitric oxide synthase, increased expression of endothelin 1, a changed balance between the production of vasodilator and vasoconstrictor prostanoids, and induction of adhesion molecules. This review describes how these and other changes influence endothelium-dependent vasodilation in patients with insulin resistance and diabetes. The clinical utility of endothelial function testing and future therapeutic targets is also discussed.

Key Points

  • Endothelial vasomotor function is mediated by factors secreted from vascular endothelial cells, including nitric oxide, prostacyclin, endothelin 1, thromboxane, and other molecules

  • Insulin resistance and diabetes are characterized by endothelial dysfunction, with decreased production of vasodilatory factors and increased production of vasoconstricting factors

  • Changes in cellular signaling and secreted factors, among them vasomotor factors, contribute to an increased risk of vasothrombotic complications in diabetes

  • Atherosclerotic complications can be prevented by interfering with endothelial cell signaling and endothelium-derived factors

  • Endothelial function can be measured noninvasively in patients and future research might allow such testing to predict the efficacy of drug and lifestyle interventions

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Figure 1: Proposed mechanisms for production of endothelium-derived vasodilators and vasoconstrictors in health (left) and in insulin resistance and diabetes (right).

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Acknowledgements

A Mentor-Based Postdoctoral Fellowship Award to GL King from the American Diabetes Association (7-02-MN-12) supports C Rask-Madsen. This work is also supported by grants from the National Institutes of Health to GL King (DK53105 and DK71359). The Joslin Diabetes Center is the recipient of a Diabetes and Endocrinology Research Center Grant (5 P30 DK36836).

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Correspondence to George L King.

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GL King has received research support from Eli Lilly Co. C Rask-Madsen declared he has no competing interests.

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Rask-Madsen, C., King, G. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Nat Rev Endocrinol 3, 46–56 (2007). https://doi.org/10.1038/ncpendmet0366

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