Activation of AT₂ receptors prevents diabetic complications in female db/db mice by NO-mediated mechanisms.

ABSTRACT:

Background and purpose

The AT₂ receptor plays a role in metabolism by opposing the actions triggered by the AT₁ receptors. Activation of AT₂ 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 AT₂ 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 AT₂ 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 AT₂ 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.

SUBMITTER: Dominici FP 

PROVIDER: S-EPMC7520448 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature