Microvascular Management of Systemic Insulin Sensitivity
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- diabetes mellitus
- endothelial cells
- insulin-like growth factor-1
- insulin resistance
- TEA domain family member 4
Microvascular disease is a well-recognized complication of long-standing diabetes mellitus and is preceded by impaired vasoreactivity, a consequence largely of decreased endothelial cell (EC) generation of NO. This loss of normal vasodilation is evident particularly in EC responses to insulin and may arise early in states of obesity and insulin resistance.1–3 In addition, ECs serve as purveyors of other paracrine signals, with targets beyond vascular cells. Thus, a broader scope of endothelial function is being recognized, with increased attention now focused on the dynamic interactions between the microvasculature and surrounding tissues. Indeed, recent findings suggest that ECs might be critical metabolic mediators, obscuring a clear boundary between vascular biology and metabolism. Accordingly, dysregulated EC function may prove to be not only a sequela of diabetes mellitus but also a contributing factor to the pathogenesis and progression of metabolic disease.
Article, see p 991
The role of ECs in regulating systemic insulin sensitivity has received relatively little attention to date because animals with EC-targeted deletion of proteins are required to observe such a role, and generation of such animals is time-consuming. However, mouse models expressing Cre recombinase under control of EC-selective promoters/enhancers, combined with mouse models with floxed target genes, are now becoming more routinely used for metabolic studies. The most commonly used promoter is the Tie2 promoter, which encodes endothelial-specific receptor tyrosine kinase,4 but other promoters are used as well. The Tie2 promoter is active in ECs but also in hematopoietic cells and female germ cells. Such mouse models have begun to reveal a metabolic role for ECs. Thus, when fed a high-fat diet, …