Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes

Liana K Billings; Kathleen A Jablonski; Qing Pan; Paul W Franks; Ronald B Goldberg; Marie-France Hivert; Steven E Kahn; William C Knowler; Christine G Lee; Jordi Merino; Alicia Huerta-Chagoya; Josep M Mercader; Sridharan Raghavan; Zhuqing Shi; Shylaja Srinivasan; Jianfeng Xu; Jose C Florez; Miriam S Udler

doi:10.2337/db23-0761

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Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes

Journal article

Peer reviewed

Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes

Liana K Billings, Kathleen A Jablonski, Qing Pan, Paul W Franks, Ronald B Goldberg, Marie-France Hivert, Steven E Kahn, William C Knowler, Christine G Lee, Jordi Merino, …

Diabetes (New York, N.Y.)

2024-05-17

DOI: https://doi.org/10.2337/db23-0761

PMID: 38758294

Appears in Miller School of Medicine - Latest Publications

Abstract

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, 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 β-cell cluster pPS had worsening in measures of β-cell function.

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Title: Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes
Creators: Liana K Billings - NorthShore University HealthSystem
Kathleen A Jablonski - George Washington University
Qing Pan - George Washington University
Paul W Franks - Skåne University Hospital
Ronald B Goldberg - University of Miami
Marie-France Hivert - Massachusetts General Hospital
Steven E Kahn - VA Puget Sound Health Care System
William C Knowler - National Institute of Diabetes and Digestive and Kidney Diseases
Christine G Lee - National Institute of Diabetes and Digestive and Kidney Diseases
Jordi Merino - Massachusetts General Hospital
Alicia Huerta-Chagoya - Massachusetts General Hospital
Josep M Mercader - Broad Institute
Sridharan Raghavan - VA Eastern Colorado Health Care System
Zhuqing Shi - NorthShore University HealthSystem
Shylaja Srinivasan - University of California, San Francisco
Jianfeng Xu - NorthShore University HealthSystem
Jose C Florez - Massachusetts General Hospital
Miriam S Udler - Massachusetts General Hospital
Publication Details: Diabetes (New York, N.Y.)
Grant note: NorthShore Auxiliary Scholars Award from NorthShore University HealthSystemNIDDK, NIH: U01 DK048489, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, U01 DK048400 American Diabetes AssociationNutrition Obesity Research Center at Harvard: P30 DK040561 NIH: UG1 HD107691 Boettcher FoundationU.S. Department of Veterans Affairs: IK2-CX001907 National Human Genome Research Institute: U01HG011723 National Heart, Lung, and Blood Institute, NIH: K24 HL157960 Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institute on AgingNational Eye InstituteNational Heart, Lung, and Blood InstituteNational Cancer InstituteOffice of Research on Women's HealthNational Institute on Minority Health and Health DisparitiesCenters for Disease Control and PreventionNovo Nordisk FoundationNIDDK, including its Intramural Research ProgramIndian Health ServiceGeneral Clinical Research Center program, National Center for Research ResourcesDepartment of Veterans AffairsMerck KGaA provided medication for DPPOSLifeScanMerck-Medco Managed CareNike Sports Marketing, Slim Fast FoodsQuaker Oats CompanyHenry M. Jackson FoundationA NIH: U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437
L.K.B. is supported by the NorthShore Auxiliary Scholars Award from NorthShore University HealthSystem. M.S.U. was supported by NIDDK, NIH, grant K23DK114551. J.M. was partially supported by the American Diabetes Association (7-21-JDFM-005), the Nutrition Obesity Research Center at Harvard (P30 DK040561), and NIH (UG1 HD107691). S.R. is supported by a Webb-Waring Biomedical Research Award from the Boettcher Foundation and by U.S. Department of Veterans Affairs award IK2-CX001907. J.M.M. is supported by American Diabetes Association grant 11-22-ICTSPM-16 and National Human Genome Research Institute grant U01HG011723. A.H.-C. is supported by American Diabetes Association grant 11-23-PDF-35. J.C.F. is supported by National Heart, Lung, and Blood Institute, NIH, grant K24 HL157960. Genotyping in the DPP was supported by NIDDK, NIH, grant R01 DK072041 to J.C.F. Research reported in this publication was supported by the NIDDK, NIH, under award nos. U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400, through provision of funding during DPP and DPPOS to the clinical centers and the Coordinating Center for the design and conduct of the study and collection, management, analysis, and interpretation of data. Funding was also provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute on Aging; the National Eye Institute; the National Heart, Lung, and Blood Institute; the National Cancer Institute; the Office of Research on Women's Health; the National Institute on Minority Health and Health Disparities; the Centers for Disease Control and Prevention; and the American Diabetes Association. Genetic analyses in the DPP were funded in part through a grant to P.W.F. from the Novo Nordisk Foundation. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center program, National Center for Research Resources, and Department of Veterans Affairs supported data collection at many of the clinical centers. Merck KGaA provided medication for DPPOS. DPP and DPPOS have also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, LifeScan, Health o meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck and Co., Nike Sports Marketing, Slim Fast Foods, and The Quaker Oats Company. The Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The sponsor of this study was represented on the Steering Committee and played a part in study design, how the study was done, and publication.
Academic Unit: Miller School of Medicine; Diabetes Research Institute (DRI)
Language: English
Resource Type: Journal article
PMID: 38758294
Record Identifier: 991032042201702976