Investigating increased shear stress and physical activity as strategies to improve vascular insulin sensitivity
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Impaired vasodilator actions of insulin in type 2 diabetes (T2D) result in blunted insulin-stimulated skeletal muscle capillary perfusion which limits nutrient delivery and contributes to glycemic dysregulation. Thus, identification of strategies to improve vascular insulin sensitivity in T2D is paramount. Evidence suggests that acute bouts of exercise may improve insulin-stimulated vasodilation in vascular beds exposed to increases in blood flow. Thus, I hypothesize that increases in blood flow-associated shear stress, in the absence of muscle contraction, on the vascular endothelium renders the vasculature more insulin-responsive. This idea was tested in (i) cultured endothelial cells, (ii) isolated and pressurized skeletal muscle arterioles from swine, and (iii) humans. I found that, in confirmation of my hypothesis, previous exposure to shear stress primed the vasculature to become more insulin-responsive across all three tested models. Next, I sought to determine whether impaired skeletal muscle capillary perfusion in response to insulin in T2D was determined by an impairment in the vasodilation of upstream resistance arteries. Interestingly, the data indicated that increased leg vascular conductance, an indication of resistance artery vasodilation, during a hyperinsulinemic-euglycemic clamp was positively correlated with insulin-stimulated skeletal muscle capillary perfusion in T2D, but not in healthy subjects, suggesting that insulin-stimulated muscle perfusion in T2D is in part determined by vasodilation of resistance arteries. And finally, the hypothesis that indices of microvascular insulin resistance and overall vascular dysfunction in T2D would be improved by participation in an eight-week exercise program, in the form of increased walking, was interrogated. Despite an improvement in popliteal artery flow-mediated dilation, microvascular insulin resistance was not improved in T2D following an eight-week walking program. In conclusion, I provide evidence to suggest that increased shear stress subsequently renders the vascular endothelium more insulin-responsive, that individuals with T2D increase skeletal muscle perfusion via a divergent mechanism compared to healthy subjects, and that an exercise program in the form of 8-weeks of walking was not sufficient to improve skeletal muscle microvascular insulin resistance in individuals with T2D.
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