Endocrine Abstracts

Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin’s actions go beyond metabolic cells and also involve blood vessels, where it increases capillary flow velocity and delivery of insulin and nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibited insulin signaling in human endothelial cells through PTP1B-mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial NO-synthase activation and skeletal muscle perfusion were increased. Treatment of lean mice with adrenomedullin mimicked the effect of obesity and induced systemic insulin resistance through the endothelial adrenomedullin receptor. Endothelial loss or blockade of the adreno-medullin receptor improved obesity-induced insulin resistance. This identifies a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes.