Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes
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.
Authors
- Lee S. Weinstein (ORCID: https://orcid.org/0000-0002-1899-5152)
- Diana Campos (ORCID: https://orcid.org/0000-0002-3272-9360)
- Alfredo Martı́nez (ORCID: https://orcid.org/0000-0003-4882-4044)
- Kenneth Anthony Roquid (ORCID: https://orcid.org/0000-0001-8659-3465)
- Shengpeng Wang (ORCID: https://orcid.org/0000-0002-9030-1821)
- Min Chen (ORCID: https://orcid.org/0000-0001-8267-8963)
- Rémy Bonnavion (ORCID: https://orcid.org/0000-0002-7389-4282)
- Mohamad Wessam Alnouri (ORCID: https://orcid.org/0009-0008-7760-399X)
- Miloslav Šanda (ORCID: https://orcid.org/0000-0002-7735-3635)
- Haruya Kawase (ORCID: https://orcid.org/0000-0002-8927-0896)
- Mario Looso (ORCID: https://orcid.org/0000-0003-1495-9530)
- Stefan Offermanns (ORCID: https://orcid.org/0000-0001-8676-6805)
- Haaglim Cho (ORCID: https://orcid.org/0000-0002-6577-5320)
- Chien-Cheng Lai (ORCID: https://orcid.org/0009-0005-0948-558X)
Institutions
- Goethe University Frankfurt (DE)
- National Institutes of Health (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Max Planck Institute for Heart and Lung Research (DE)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- German Centre for Cardiovascular Research (DE)
- Center for Biomedical Research of La Rioja (ES)
- Cardio-Pulmonary Institute (DE)
Publication Details
- Journal
- Science
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1126/science.adr4731
- Citations
- 38
- Primary Topic
- Neuropeptides and Animal Physiology
- Type
- article
- Field-Weighted Citation Impact
- 32.73