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In this study, we aimed to provide a deep understanding of the molecular mechanisms that underpin the cellular and physiological impacts of\n                    <jats:italic toggle=\"yes\">GIPR<\/jats:italic>\n                    coding variation by studying 30\n                    <jats:italic toggle=\"yes\">GIPR<\/jats:italic>\n                    coding variants in cellular models and pancreatic islets. Many variants showed impaired GIP-induced cyclic adenosine monophosphate responses, and population-based association analysis highlighted that these loss-of-function variants decrease body mass index but increase glycemia. In many cases, reduced function was partly driven by reduced expression at the cell surface due to impaired stability and redirection toward proteasomal degradation. Molecular dynamics simulations suggest distinct variant-induced perturbations in inter- and intrahelical interactions, which interfere with receptor stability. This study highlights the mechanisms and consequences of\n                    <jats:italic toggle=\"yes\">GIPR<\/jats:italic>\n                    coding variation, which may have implications for the therapeutic targeting of this receptor.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aec3372","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:58:46Z","timestamp":1788544726000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Glycemic and bodyweight effects of\n                    <i>GIPR<\/i>\n                    coding variation reflect differences in surface expression and intrinsic functional impairment"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2874-5608","authenticated-orcid":true,"given":"Yusman","family":"Manchanda","sequence":"first","affiliation":[{"name":"Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London W12 0NN, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6770-5425","authenticated-orcid":true,"given":"Rofaida","family":"Desoki","sequence":"additional","affiliation":[{"name":"MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Box 285 Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK."},{"name":"Genetics Department and Clinical Genomics Centre, Faculty of Medicine, Alexandria University, Alexandria, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9671-1533","authenticated-orcid":true,"given":"Eugene J.","family":"Gardner","sequence":"additional","affiliation":[{"name":"MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Box 285 Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6483-3771","authenticated-orcid":true,"given":"John R. 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