Abstract

Objectives: The angiotensin converting enzyme 2 (ACE2)/angiotensin-(1- 7)/Mas pathway has been expected to act as a protective arm of the renin-angiotensin system. Recently, the role of ACE2 in glucose metabolism has been highlighted. We previously reported that olmesartan increases ACE2 expression in injured arteries. Therefore, we hypothesized that treatment with olmesartan would improve glucose metabolism via ACE2 activation. Here, we investigated the effect of olmesartan on glucose metabolism using ACE2-deficient mice (ACE2KO).

Methods: Ten-week-old WT and ACE2-deficient mice (ACE2KO) were employed in this study. Olmesartan or valsartan was administered intraperitoneally at a dose of 1.5 mg/kg/day in 8 weeks old mice. Insulin resistance was evaluated by oral glucose tolerance test and insulin tolerance test. Morphological changes in adipose tissue as well as adipocyte differentiation and inflammatory response and histological changes in the pancreas were examined.

Results: ACE2KO showed significantly higher fasting blood glucose level and blood glucose level at 30 min after glucose load in the oral glucose tolerance test. Treatment with olmesartan reduced blood glucose level at 30 min after glucose load in both WT and ACE2KO, but valsartan did not. Treatment with olmesartan increased adipocyte number and reduced mean adipocyte size only in WT, but not in ACEKO. Treatment with olmesartan also prevented the reduced size of pancreatic islets in ACE2KO.

Conclusion: The present study demonstrated that ACE2KO exhibited abnormal glucose metabolism. Treatment with olmesartan improved glucose metabolism in WT more than in ACEKO mice, indicating the possible existence of an ACE2-dependent pathway induced by olmesartan.

Keywords: ACE2, olmesartan, glucose metabolism, pancreas, glucose tolerance, adipocyte.

Graphical Abstract