ACE2 gene therapy improves glucose tolerance and insulin sensitivity in high fat diet‐fed mice

High fat diet (HFD) has been reported to activate the renin‐angiotensin system (RAS) which in turn might mediate type 2 diabetes (T2D). ACE2 is an enzyme that counteracts the detrimental effects mediated by RAS over activity. To explore the role of ACE2 in glycemic control , ACE2 knockout (KO) and wildtype (WT) mice (2 months old, N = 5/group) were fed with HFD for 16 weeks. After 16 weeks, fasting blood glucose (FBG, mg/dl), plasma insulin (PI, ng/ml) levels and glucose tolerance (AUC, mg/dl*120) were assessed in those mice. ACE2 KO mice exhibited significantly higher ( P <0.05) FBG (262.8 ±31.95 vs. 141.0 ±7.05), PI (8.07 ±0.6 vs. 5.08 ±0.8) and AUC (63862 ±1699 vs. 52037 ±2264) vs. WT mice, suggesting that knockout mice have an enhanced propensity to develop T2D. To examine the therapeutic potential of ACE2 in diabetic WT mice, HFD‐fed animals were treated (at 16 th week) with intra‐pancreatic administration of an adenovirus expressing hACE2, or GFP, gene. After 2 weeks, ACE2‐treated mice showed significant reductions in FBG (138.0 ±22.5 vs. 224.6 ±27.13), PI (5.4 ±1.0 vs. 8.5 ±0.5) and AUC (44702 ±1571 vs. 52099 ±2273) vs. GFP‐treated mice, suggesting therapeutic efficacy of ACE2 in ameliorating uncontrolled glycemia. In conclusion, ACE2 plays a beneficial role in the regulation of glycemia and could be a potential therapeutic target to improve glucose tolerance and insulin sensitivity in diabetes. Support: American Diabetes Association (1_10_BS_93) and NIH/NIDDK ( DK084466 )