Insulin resistance is a central pathomechanism of obesity-induced type 2 diabetes. Insulin’s actions are not restricted to metabolic target cells but also involve the vascular endothelium where insulin acts to increase blood flow and delivery of insulin as well as nutrients to metabolic target tissues such as skeletal muscle.
The importance of endothelial insulin signaling for insulin resistance and its relevance as a potential therapeutic target are, however, unclear. Haaglim Cho from Stefan Offermanns’ group and colleagues show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibits insulin signaling in human endothelial cells through protein kinase A-mediated phosphorylation and activation of protein tyrosine phosphatase 1B resulting in dephosphorylation of the endothelial insulin receptor. The adrenomedullin binding protein complement factor H whose levels are also elevated in obese humans and mice promotes adrenomedullin effects.
In obese mice with endothelium-specific deficiency of the adrenomedullin receptor or the G-protein Gs, 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 which depended on the endothelial adrenomedullin receptor. Finally, they found that endothelium-specific loss of the adrenomedullin receptor or of Gs as well as treatment with an adrenomedullin receptor antagonist improved obesity-induced insulin resistance.
These data highlight the relevance of endothelial insulin resistance for systemic insulin resistance in type 2 diabetes. In addition, the study identified a mechanism underlying obesity-induced endothelial and systemic insulin resistance and suggest approaches to prevent and treat obesity-associated type 2 diabetes.
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