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We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (\u03b2-cell, proinsulin, liver\/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms. Associations were tested with general linear models and Cox regression with adjustment for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher \u03b2-cell pPS was associated with lower insulinogenic index and corrected insulin response at 1-year follow-up with adjustment for baseline measures (effect per pPS SD \u22120.04, P = 9.6 \u00d7 10\u22127, and \u22128.45 \u03bcU\/mg, P = 5.6 \u00d7 10\u22126, respectively) and with increased diabetes incidence with adjustment for BMI at nominal significance (hazard ratio 1.10 per SD, P = 0.035). The liver\/lipid pPS was associated with reduced 1-year baseline-adjusted triglyceride levels (effect per SD \u22124.37, P = 0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the \u03b2-cell cluster pPS had worsening in measures of \u03b2-cell function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                  <\/jats:sec>","DOI":"10.2337\/db23-0761","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T10:59:17Z","timestamp":1715943557000},"page":"1352-1360","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":11,"title":["Increased Genetic Risk for \u03b2-Cell Failure Is Associated With \u03b2-Cell Function Decline in People With Prediabetes"],"prefix":"10.2337","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7991-3010","authenticated-orcid":false,"given":"Liana K.","family":"Billings","sequence":"first","affiliation":[{"name":"1Division of Endocrinology, Department of Medicine, NorthShore University HealthSystem\/Endeavor Health, Skokie, IL"},{"name":"2Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"Jablonski","sequence":"additional","affiliation":[{"name":"3Biostatistics Center, George Washington University, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1253-0490","authenticated-orcid":false,"given":"Qing","family":"Pan","sequence":"additional","affiliation":[{"name":"3Biostatistics Center, George Washington University, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose C.","family":"Florez","sequence":"additional","affiliation":[{"name":"8Diabetes Unit, Massachusetts General Hospital, Boston, MA"},{"name":"12Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA"},{"name":"13Program in Metabolism and Program in Medical and Population Genetics, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA"},{"name":"14Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W.","family":"Franks","sequence":"additional","affiliation":[{"name":"4Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Science, Lund University, Sk\u00e5ne University Hospital, Malm\u00f6, Sweden"},{"name":"5Harvard T.H. Chan School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald B.","family":"Goldberg","sequence":"additional","affiliation":[{"name":"6Leonard M. Miller School of Medicine, University of Miami, Miami, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-France","family":"Hivert","sequence":"additional","affiliation":[{"name":"7Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA"},{"name":"8Diabetes Unit, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven E.","family":"Kahn","sequence":"additional","affiliation":[{"name":"9Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Knowler","sequence":"additional","affiliation":[{"name":"10National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine G.","family":"Lee","sequence":"additional","affiliation":[{"name":"11Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Merino","sequence":"additional","affiliation":[{"name":"8Diabetes Unit, Massachusetts General Hospital, Boston, MA"},{"name":"12Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA"},{"name":"13Program in Metabolism and Program in Medical and Population Genetics, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA"},{"name":"14Department of Medicine, Harvard Medical School, Boston, MA"},{"name":"15Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Huerta-Chagoya","sequence":"additional","affiliation":[{"name":"12Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA"},{"name":"13Program in Metabolism and Program in Medical and Population Genetics, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep M.","family":"Mercader","sequence":"additional","affiliation":[{"name":"8Diabetes Unit, Massachusetts General Hospital, Boston, MA"},{"name":"12Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA"},{"name":"13Program in Metabolism and Program in Medical and Population Genetics, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA"},{"name":"14Department of Medicine, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridharan","family":"Raghavan","sequence":"additional","affiliation":[{"name":"16Department of Veterans Affairs Eastern Colorado Health Care System, Aurora, CO"},{"name":"17Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuqing","family":"Shi","sequence":"additional","affiliation":[{"name":"18Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shylaja","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"19Department of Pediatrics, University of California, San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Xu","sequence":"additional","affiliation":[{"name":"18Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-9162","authenticated-orcid":false,"given":"Miriam S.","family":"Udler","sequence":"additional","affiliation":[{"name":"8Diabetes Unit, Massachusetts General Hospital, Boston, MA"},{"name":"12Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA"},{"name":"13Program in Metabolism and Program in Medical and Population Genetics, Eli and Edythe L. 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