Activation of AT 2 receptors prevents diabetic complications in female db/db mice by NO‐mediated mechanisms

Background and Purpose The AT 2 receptor plays a role in metabolism by opposing the actions triggered by the AT 1 receptors. Activation of AT 2 receptors has been shown to enhance insulin sensitivity in both normal and insulin resistance animal models. In this study, we investigated the mechanism by which AT 2 receptors activation improves metabolism in diabetic mice. Experimental Approach Female diabetic (db/db) and non‐diabetic (db/+) mice were treated for 1 month with the selective AT 2 agonist, compound 21 (C21, 0.3 mg·kg −1 ·day −1 , s.c.). To evaluate whether the effects of C21 depend on NO production, a subgroup of mice was treated with C21 plus a sub‐pressor dose of the NOS inhibitor l ‐NAME (0.1 mg·ml −1 , drinking water). Key Results C21‐treated db/db mice displayed improved glucose and pyruvate tolerance compared with saline‐treated db/db mice. Also, C21‐treated db/db mice showed reduced liver weight and decreased hepatic lipid accumulation compared with saline‐treated db/db mice. Insulin signalling analysis showed increased phosphorylation of the insulin receptor, Akt and FOXO1 in the livers of C21‐treated db/db mice compared with saline‐treated counterparts. These findings were associated with increased adiponectin levels in plasma and adipose tissue and reduced adipocyte size in inguinal fat. The beneficial effects of AT 2 receptors activation were associated with increased eNOS phosphorylation and higher levels of NO metabolites and were abolished by l ‐NAME. Conclusion and Implications Chronic C21 infusion exerts beneficial metabolic effects in female diabetic db/db mice, alleviating type 2 diabetes complications, through a mechanism that involves NO production.