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Cell division regulators MAD2, BUBR1, and p31comet promote IR endocytosis on insulin stimulation. Here, we show that genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis, increases IR levels, and prolongs insulin action at the cell surface. This in turn causes a defect in insulin clearance and increases circulating insulin levels, unexpectedly increasing glucagon levels, which alters glucose metabolism modestly. Disruption of the IR-MAD2 interaction increases serum fatty acid concentrations and hepatic fat accumulation in fasted male mice. Furthermore, disruption of the IR-MAD2 interaction distinctly changes metabolic and transcriptomic profiles in the liver and adipose tissues. Our findings establish the function of cell division regulators in insulin signaling and provide insights into the metabolic functions of IR endocytosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>The physiological role of IR endocytosis in insulin sensitivity remains unclear. Disruption of the IR-MAD2 interaction delays IR endocytosis and prolongs insulin signaling. IR-MAD2 controls insulin clearance and glucose metabolism. IR-MAD2 maintains energy homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db23-0314","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T18:21:22Z","timestamp":1695147682000},"page":"1781-1794","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":9,"title":["MAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis"],"prefix":"10.2337","volume":"72","author":[{"given":"Junhee","family":"Park","sequence":"first","affiliation":[{"name":"1Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Hall","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Hubbard","sequence":"additional","affiliation":[{"name":"2Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Traci","family":"LaMoia","sequence":"additional","affiliation":[{"name":"2Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Gaspar","sequence":"additional","affiliation":[{"name":"2Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Nasiri","sequence":"additional","affiliation":[{"name":"2Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Li","sequence":"additional","affiliation":[{"name":"3Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanrui","family":"Zhang","sequence":"additional","affiliation":[{"name":"3Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"4Department of Urology and Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Haeusler","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY"},{"name":"5Naomi Berrie Diabetes Center, Columbia University, New York, NY"},{"name":"6Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6874-3949","authenticated-orcid":false,"given":"Domenico","family":"Accili","sequence":"additional","affiliation":[{"name":"5Naomi Berrie Diabetes Center, Columbia University, New York, NY"},{"name":"6Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1529-5668","authenticated-orcid":false,"given":"Gerald I.","family":"Shulman","sequence":"additional","affiliation":[{"name":"2Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, 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