Downregulation of the Vascular Insulin Signaling Pathway may Contribute to Hyperglycemia Following High Fat Intake

Abstract

Type 2 diabetes (T2D) prevalence worldwide has increased markedly and is a major threat to global health. Insulin resistance is a key factor in the pathogenesis of T2D. Prior studies in our laboratory have shown that feeding rats a high fat diet (HFD) for 6 weeks results in increased adiposity, hyperglycemia, insulin resistance, and impaired nitric oxide (NO)‐dependent vasodilation of small resistance arteries, all major risk factors for T2D and CVD. While HFD induced insulin resistance is well‐characterized in skeletal muscle, the impacts of HFD on insulin‐mediated vasodilation is less understood. We hypothesized that feeding adult male Sprague‐Dawley rats a HFD (60% kcal from fat) for 6 weeks would downregulate the insulin‐mediated vasodilatory pathway (i.e., IRS‐1, PI3K, Akt, and eNOS) in comparison to chow‐fed controls. Western blot analyses of isolated aorta indicate that protein expression of IRS‐1, p‐PI3K(p85), total Akt, p‐Akt(t308), and p‐Akt (s473) were not significantly affected by HFD. In contrast, p‐IRS‐1 expression was modestly but not significantly (p=0.089) decreased. The expression of p‐PI3K(p55) and p‐eNOS were significantly diminished (p=0.045 and p=0.032, respectively) in HFD aortas compared to chow‐fed controls. These results suggest that endothelial dysfunction and hyperglycemia observed in rats fed a HFD may be attributed in part to reduced expression of vascular insulin signaling pathway intermediates resulting in reduced blood flow and glucose delivery. This study was funded in part by the Graduate and Professional Student Association, ASU.