Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes

• 成果类型: Article
• 署名作者: Cho, Haaglim; Lai, Chien-Cheng; Bonnavion, Remy; Alnouri, Mohamad Wessam; Wang, ShengPeng; Roquid, Kenneth Anthony; Kawase, Haruya; Campos, Diana; Chen, Min; Weinstein, Lee S.; Martinez, Alfredo; Looso, Mario; Sanda, Miloslav; Offermanns, Stefan
• 署名单位: Max Planck Society; Xi'an Jiaotong University; Max Planck Society; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); Max Planck Society; Goethe University Frankfurt; German Centre for Cardiovascular Research
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8904
• DOI: 10.1126/science.adr4731
• 发表日期: 2025-02-07
• 页码: 674-682
• 关键词: skeletal-muscle vasodilation; complement factor-h; glucose-tolerance; binding-protein; in-vivo; cells; mechanisms; transport; brain; phosphorylation

摘要

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 blood flow 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 protein-tyrosine phosphatase 1B-mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial nitric oxide-synthase activation and skeletal muscle perfusion were increased. Treating mice with adrenomedullin mimicked the effect of obesity and induced endothelial and systemic insulin resistance. Endothelial loss or blockade of the adrenomedullin receptor improved obesity-induced insulin resistance. These findings identify a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes.