title: Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure.
abstract: 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.
authors.affiliation: From the Department of Molecular Physiology and Biophysics (I.M.W., Y.F.O., D.P.B., D.H.W.) and Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (I.B., A.C.A.).
authors.forename: Ian M
authors.initials: IM
authors.lastname: Williams
authors.affiliation: From the Department of Molecular Physiology and Biophysics (I.M.W., Y.F.O., D.P.B., D.H.W.) and Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (I.B., A.C.A.).
authors.forename: Yolanda F
authors.initials: YF
authors.lastname: Otero
authors.affiliation: From the Department of Molecular Physiology and Biophysics (I.M.W., Y.F.O., D.P.B., D.H.W.) and Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (I.B., A.C.A.).
authors.forename: Deanna P
authors.initials: DP
authors.lastname: Bracy
authors.affiliation: From the Department of Molecular Physiology and Biophysics (I.M.W., Y.F.O., D.P.B., D.H.W.) and Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (I.B., A.C.A.).
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
authors.affiliation: From the Department of Molecular Physiology and Biophysics (I.M.W., Y.F.O., D.P.B., D.H.W.) and Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (I.B., A.C.A.).
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.affiliation: From the Department of Molecular Physiology and Biophysics (I.M.W., Y.F.O., D.P.B., D.H.W.) and Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (I.B., A.C.A.). amy.arnold@vanderbilt.edu.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Arnold
mesh_terms: D000704:Analysis of Variance; D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001795:Blood Pressure Determination / Q000379:methods; D001823:Body Composition / Q000502:physiology; D002318:Cardiovascular Diseases / Q000517:prevention & control; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015309:Glucose Clamp Technique; D006334:Heart Function Tests; D006439:Hemodynamics / Q000502:physiology; D006973:Hypertension / Q000517:prevention & control; D055104:Infusions, Subcutaneous; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000503:physiopathology; D010446:Peptide Fragments / Q000494:pharmacology*; D011897:Random Allocation; D012016:Reference Values; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D010446:Peptide Fragments; D000803:Angiotensin I; C118790:angiotensin I (1-7)
keywords: hypertension; insulin resistance; metabolism; obesity; renin–angiotensin system