Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure.

Williams IM, Otero YF, Bracy DP, Wasserman DH, Biaggioni I, Arnold AC
Hypertension. 2016 67 (5): 983-91

PMID: 26975707 · PMCID: PMC4833535 · DOI:10.1161/HYPERTENSIONAHA.115.06935

Angiotensin-(1-7) improves glycemic control in animal models of cardiometabolic syndrome. The tissue-specific sites of action and blood pressure dependence of these metabolic effects, however, remain unclear. We hypothesized that Ang-(1-7) improves insulin sensitivity by enhancing peripheral glucose delivery. Adult male C57BL/6J mice were placed on standard chow or 60% high-fat diet for 11 weeks. Ang-(1-7) (400 ng/kg per minute) or saline was infused subcutaneously during the last 3 weeks of diet, and hyperinsulinemic-euglycemic clamps were performed at the end of treatment. High-fat fed mice exhibited modest hypertension (systolic blood pressure: 137 ± 3 high fat versus 123 ± 5 mm Hg chow;P=0.001), which was not altered by Ang-(1-7) (141 ± 4 mm Hg;P=0.574). Ang-(1-7) did not alter body weight or fasting glucose and insulin in chow or high-fat fed mice. Ang-(1-7) increased the steady-state glucose infusion rate needed to maintain euglycemia in high-fat fed mice (31 ± 5 Ang-(1-7) versus 16 ± 1 mg/kg per minute vehicle;P=0.017) reflecting increased whole-body insulin sensitivity, with no effect in chow-fed mice. The improved insulin sensitivity in high-fat fed mice was because of an enhanced rate of glucose disappearance (34 ± 5 Ang-(1-7) versus 20 ± 2 mg/kg per minute vehicle;P=0.049). Ang-(1-7) enhanced glucose uptake specifically into skeletal muscle by increasing translocation of glucose transporter 4 to the sarcolemma. Our data suggest that Ang-(1-7) has direct insulin-sensitizing effects on skeletal muscle, independent of changes in blood pressure. These findings provide new insight into mechanisms by which Ang-(1-7) improves insulin action, and provide further support for targeting this peptide in cardiometabolic disease.

MeSH Terms (25)

Analysis of Variance Angiotensin I Animals Blood Glucose Blood Pressure Determination Body Composition Cardiovascular Diseases Diet, High-Fat Disease Models, Animal Dose-Response Relationship, Drug Drug Administration Schedule Glucose Clamp Technique Heart Function Tests Hemodynamics Hypertension Infusions, Subcutaneous Insulin Resistance Male Mice Mice, Inbred C57BL Obesity Peptide Fragments Random Allocation Reference Values Renin-Angiotensin System

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