ACE 2: A potential therapeutic target for Angiotensin II‐mediated insulin resistance and glucose intolerance

Abstract

Over activation of the renin‐angiotensin system (RAS) plays a key role in diabetes. ACE2 has been reported to counteract the pathophysiological effects of RAS over activity. To clarify the role of ACE2 in glucose homeostasis, ACE2 KO and control mice (5 months old, n=5/group) were infused with AngII (osmotic pump: 600 ng/kg/min); insulin levels (ng/ml) and glucose tolerance (AUC: mg/dl*120) were assessed after 14 days infusion. KO mice manifested significantly (P<0.05) higher hyperinsulinemia (6.2 ±0.49 vs. 4.5 ±0.23) and glucose intolerance (55300 ±1387 vs. 43550 ±1735) compared to controls, suggesting their hypersensitivity to diabetes. To assess the therapeutic potential of ACE2, βTC‐ 3 cells (mouse insulinoma) were subjected to glucose stimulated insulin secretion assay (2.8, 16, 25 mM glucose) in which AngII significantly (P<0.05) decreased insulin secretion vs. control group (1.01 ±0.01 vs. 1.84 ±0.12; 1.57 ±0.15 vs. 2.78 ±0.05; 1.7 ±0.08 vs. 2.64 ±0.05 ng/ml, respectively). In cells pretreated with an adenovirus over expressing ACE2, insulin secretion was restored (1.75 ±0.14; 2.81 ±0.22; 3.25 ±0.22 ng/ml, respectively), suggesting ACE2 can prevent the Ang‐II mediated inhibitory effect. In conclusion ACE2 is important in the regulation of glucose homeostasis and could be a potential therapeutic target to ameliorate insulin resistance and glucose intolerance resulting from RAS over activation.LSUHSC research enhancement fund.