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Published on: January 7, 2018
Insulin resistance and endothelial cell dysfunction: studies in mammalian models
Mark T Kearney1, Edward R Duncan, Mathew Kahn
1Cardiovascular and Diabetes Research, The Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. m.t.kearney@leeds.ac.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.
Insights
Insulin resistance contributes to cardiovascular atherosclerosis by impairing endothelial nitric oxide production. This review explores insulin
Area of Science:
- Cardiovascular pathophysiology and metabolic disorders.
Background:
- Type 2 diabetes and obesity are primary drivers of cardiovascular atherosclerosis.
- Insulin resistance in traditional tissues is well-established, but its role in non-canonical tissues like the endothelium is less understood.
- Endothelial insulin resistance may contribute to atherosclerosis independently of diabetes and obesity.
Purpose of the Study:
- To review the association between insulin resistance and endothelial cell function.
- To explore the role of endothelial insulin resistance in vascular pathophysiology.
- To highlight the contribution of murine models to understanding insulin resistance-related vasculopathy.
Main Methods:
- Review of human studies and gene-modified mouse models.
- Analysis of the link between insulin resistance and nitric oxide bioactivity.
- Examination of insulin's effects on endothelial cells and nitric oxide production.
Main Results:
- Insulin resistance is linked to reduced nitric oxide bioactivity in endothelial cells.
- Endothelial cells possess insulin receptors and respond to insulin with nitric oxide production.
- Studies in humans and mice show a strong correlation between insulin resistance and impaired nitric oxide function.
Conclusions:
- Endothelial insulin resistance is a significant factor in the development of atherosclerosis.
- Impaired nitric oxide bioactivity due to insulin resistance contributes to vascular dysfunction.
- Murine models offer valuable insights into the mechanisms linking obesity, insulin resistance, and cardiovascular disease.
