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
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