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Experimental Physiology 93.1 pp 158-163
DOI: 10.1113/expphysiol.2007.039172
© The Physiological Society 2008
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Insulin resistance and endothelial cell dysfunction: studies in mammalian models

 Mark T. Kearney1, Edward R. Duncan2, Mathew Kahn1 and Stephen B. Wheatcroft1

1 Cardiovascular and Diabetes Research, The Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, UK 2 Kings College London, London, UK

Abstract

Type 2 diabetes and obesity are major risk factors for the development of cardiovascular atherosclerosis. Resistance to the metabolic effects of insulin on its traditional target tissues (muscle, liver and adipose tissue) is a central pathogenic feature of these disorders. However, the role of insulin resistance in non-canonical tissues, such as the endothelium, is less clear. Several large studies support a role for insulin resistance in the development of premature cardiovascular atherosclerosis independent of type 2 diabetes and obesity. A key step in the initiation and progression of atherosclerosis is a reduction in the bioactivity of endothelial cell-derived nitric oxide. Nitric oxide is a signalling molecule which has a portfolio of potential antiatherosclerotic effects. The presence of insulin receptors on endothelial cells is well documented, and the endothelium has now emerged as a potentially important target tissue for insulin, with insulin-stimulated production of nitric oxide a feature of the action of insulin on endothelial cells. The role of insulin resistance at the level of the endothelial cell in vascular pathophysiology is unclear. A number of studies in humans and gene-modified mice have demonstrated a close association between insulin resistance and nitric oxide bioactivity. In this review, we discuss the link between insulin resistance and endothelial cell function in humans and demonstrate the complimentary information provided by murine models of obesity and insulin resistance in our understanding of the vasculopathy associated with type 2 diabetes and obesity.

(Received 22 June 2007; accepted after revision 21 September 2007; first published online 12 October 2007)
Corresponding author M. T. Kearney: Cardiovascular and Diabetes Research, The Leeds Institute of Genetics, Health and Therapeutics, The LIGHT Laboratories, Clarendon Way, University of Leeds, Leeds LS2 9JT, UK. Email: m.t.kearney{at}leeds.ac.uk






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