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 angiotensin-(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. Angiotensin-(1–7) [400 ng/kg/min] 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 mmHg chow; p=0.001), which was not altered by angiotensin-(1–7) [141±4 mmHg; p=0.574]. Angiotensin-(1–7) did not alter body weight or fasting glucose and insulin in chow or high-fat fed mice. Angiotensin-(1–7) increased the steady-state glucose infusion rate needed to maintain euglycemia in high-fat fed mice (31±5 angiotensin-(1–7) versus 16±1 mg/kg/min 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 due to an enhanced rate of glucose disappearance (34±5 angiotensin-(1–7) versus 20±2 mg/kg/min vehicle; p=0.049). Angiotensin-(1–7) enhanced glucose uptake specifically into skeletal muscle by increasing translocation of glucose transporter 4 to the sarcolemma. Our data suggest that angiotensin-(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 angiotensin-(1–7) improves insulin action, and provide further support for targeting this peptide in cardiometabolic disease.

Transendothelial Insulin Transport is Impaired in Skeletal Muscle Capillaries of Obese Male Mice

“…To test whether SkM IR could be detected in diet‐induced obesity (DIO) male mice, we performed intravenous insulin tolerance tests using the same protocol as intravital microscopy (i.e., anesthetized, 4‐U/kg insulin tolerance tests). Tissue glucose clearance was calculated from plasma 2[ 14 C]deoxyglucose (2[ 14 C]DG) and tissue 2[ 14 C]DG‐6‐phosphate (2[ 14 C]DGP) measurements as described previously .…”

Insulin exits skeletal muscle capillaries by fluid-phase transport

“…3 H]glucose was measured using liquid scintillation counting as described previously (45). EndoR a and R d were calculated using steady-state equations (46).…”

Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo

“…Accumulation of 2[ 14 C]deoxyglucose-6-phosphate (2[ 14 C] DGP) in gastrocnemius muscle was measured as previously described (16). Because of the difficulty of collecting samples during intravital microscopy for use in measuring 2-deoxy-D-glucose (2DG) in plasma, data are reported as 2DGP accumulation (disintegrations per minute per milligram tissue per minute).…”

“…Furthermore, the ability of insulin to activate endothelial NOS (eNOS) in endothelial cells (ECs) is impaired in mouse models of obesity and insulin resistance (14). Conversely, drugs that act on the renin-angiotensin system to enhance endothelial function and increase NO bioavailability improve glucose homeostasis (15,16). These observations suggest that insulin resistance in SkM may be linked mechanistically to reduced endothelial NO bioavailability.…”