Abstract P645: Chronic Angiotensin-(1-7) Improves Whole-Body Insulin Sensitivity in High-Fat Fed Mice by Enhancing Skeletal Muscle Glucose Uptake
Angiotensin (Ang)-(1-7) is a vasodilatory peptide implicated in the pathophysiology of hypertension, in part by opposing deleterious Ang II cardiovascular actions. Recent studies show that Ang-(1-7) restoration lowers blood pressure and improves glycemic control in animal models of cardiometabolic syndrome. The tissue-specific sites of action and blood pressure dependence for these metabolic effects, however, remain unclear. We hypothesized that Ang-(1-7) improves insulin sensitivity by enhancing peripheral glucose delivery. To test this hypothesis, adult male C57BL/6 mice were placed on standard chow or 60% high-fat diet for 11 weeks, with Ang-(1-7) [400 ng/kg/min] or saline given during the last 3 weeks of diet by subcutaneous osmotic mini-pump. Hyperinsulinemic (4 mU/kg/min) euglycemic clamps were performed in conscious, unrestrained mice at the end of the treatment period. High-fat fed mice exhibited modest hypertension (systolic blood pressure: 137±3 high-fat vs. 123±5 mmHg chow; p=0.043), which was not altered by Ang-(1-7) infusion (141±4 mmHg; p=0.516). Body weight, body composition, and fasting plasma glucose and insulin levels were not significantly different following Ang-(1-7) treatment in chow or high-fat fed mice. Ang-(1-7) increased the glucose infusion rate (GIR) needed to maintain euglycemia in high-fat fed mice (steady-state GIR: 31±5 Ang-(1-7) vs. 16±1 mg/kg/min vehicle; p=0.017) indicating enhanced whole-body insulin sensitivity, with no significant effect in chow fed mice. The improvement in insulin sensitivity in high-fat fed mice was due to an enhanced rate of whole-body glucose disappearance (Rd: 34±5 Ang-(1-7) vs. 20±2 mg/kg/min vehicle; p=0.049), with increased rates of glucose uptake in gastrocnemius, vastus, and soleus muscle. There was no effect of Ang-(1-7) on insulin-mediated suppression of hepatic glucose production. Our data shows that Ang-(1-7) has direct insulin-sensitizing effects on skeletal muscle, which are independent of changes in body weight or systemic blood pressure. These overall findings provide new insight into mechanisms by which Ang-(1-7) improves insulin action, and provide further support to targeting this peptide for treatment of cardiometabolic disease.
Author Disclosures: I.M. Williams: None. D.H. Wasserman: None. I. Biaggioni: None. A.C. Arnold: None.
- © 2015 by American Heart Association, Inc.