Transgenic mice overexpressing renin exhibit glucose intolerance and diet-genotype interactions

Abstract

Numerous animal and clinical investigations have pointed to a potential role of the renir angiotensin system (RAS) in the development of insulin resistance and diabetes in cond tions of expanded fat mass. However, the mechanisms underlying this association remai unclear. We used a transgenic mouse model overexpressing renin in the liver (RenTgMK) to examine the effects of chronic activation of RAS on adiposity and insulin sensitivity. Hepatic overexpression of renin resulted in constitutively elevated plasma angiotensin (four- to six-fold increase vs. wild-type, WT). Surprisingly, RenTgMK mice developed gl cose intolerance despite low levels of adiposity and insulinemia. The transgenics also had lower plasma triglyceride levels. Glucose intolerance in transgenic mice fed a low-fat die was comparable to that observed in high-fat fed WT mice. These studies demonstrate that overexpression of renin and associated hyperangiotensinemia impair glucose tolerance i a diet-dependent manner and further support a consistent role of RAS in the pathogenesi of diabetes and insulin resistance, independent of changes in fat mass. © 2013 Fletcher, Kalupahana, Soltani-Bejnood, Kim, Saxton, Wasser-man, DeTaeye, Voy, Quignard-Boulange and Moustaid-Moussa.