ACE2 gene therapy leads to Ang‐(1‐7)‐mediated restoration of glucose metabolism in diabetic mice

Abstract

We previously demonstrated that pancreatic ACE2 overexpression is able to improve glucose tolerance and reduce fasting blood glucose in diabetic mice. We hypothesized that ACE2 overexpression improves glucose homeostasis by enhancing pancreatic beta cell function. Diabetic db/db and lean mice (n=10/group) were infected with Ad‐hACE2 or a control adenovirus (Ad‐eGFP) and glucose homeostasis assessed after 7 days. Insulin sensitivity (area under the curve, AUC) was not different between Ad‐hACE2‐ and Ad‐eGFP‐treated db/db (50 ±3 vs. 54 ±4) and lean (31 ±9 vs. 35 ±9) mice, respectively. Ad‐hACE2 increased islet insulin content (arbitrary units) in db/db mice (92 ±7 vs. 49 ±6, P<0.01) but had no effect on lean mice (109 ±17 vs. 124 ±9) compared to Ad‐eGFP. Infusion with an Ang‐(1‐7) receptor antagonist [D‐Ala7‐Ang‐(1‐7), 600 ng/kg/min, 7 days sc], prevented Ad‐hACE2‐mediated normalization of fasting blood glucose (247 ±31 vs. 135 ±11 mg/dl, P<0.01) but had no effect on Ad‐eGFP‐treated diabetic mice (224 ±26 vs. 191 ±12 mg/dl). D‐Ala7‐Ang‐(1‐7) also prevented the Ad‐hACE2‐mediated improvement in glucose tolerance (AUC: 67 ±2 vs. 51 ±5; P<0.05) but did not affect Ad‐eGFP‐treated db/db mice (AUC: 68 ±3 vs. 72 ±2). These data indicate that ACE2 gene therapy improves pancreatic beta cell function and restores glucose homeostasis by increasing Ang‐(1‐7) receptor‐mediated signaling pathways. (NIH NS052479 and RR018766)