Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes

• DOI: 10.1126/science.adr4731
• Publication Date: 2025-02-06T18:59:31Z
• Authors: Haaglim Cho; Chien-Cheng Lai; Rémy Bonnavion; Mohamad Wessam Al...; ShengPeng Wang; Kenneth Anthony R...; Haruya Kawase; Diana Campos; Min Chen; Lee S. Weinstein; Alfredo Martínez; Mario Looso; Miloslav Sanda; Stefan Offermanns
• Keywords: Adrenomedullin; Endothelial Dysfunction

Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin’s actions go beyond metabolic cells and also involve blood vessels, where insulin increases capillary flow delivery nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans mice, inhibited signaling human endothelial through protein-tyrosine phosphatase 1B–mediated dephosphorylation the receptor. In mice lacking adrenomedullin receptor, insulin-induced nitric oxide–synthase activation skeletal muscle perfusion were increased. Treating with mimicked effect obesity induced systemic resistance. Endothelial loss or blockade receptor improved obesity-induced These findings identify mechanism underlying suggest approaches to treat