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

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

Diabetes. 2024 May 17:db230761. doi: 10.2337/db23-0761. Online ahead of print.

Authors

Liana K Billings^{1

2}, Kathleen A Jablonski³, Qing Pan³, Paul W Franks^{4

5}, Ronald B Goldberg⁶, Marie-France Hivert^{7

8}, Steven E Kahn⁹, William C Knowler¹⁰, Christine G Lee¹¹, Jordi Merino^{8

12

13

14

15}, Alicia Huerta-Chagoya^{12

13}, Josep M Mercader^{8

12

13

14}, Sridharan Raghavan^{16

17}, Zhuqing Shi¹⁸, Shylaja Srinivasan¹⁹, Jianfeng Xu¹⁸, Jose C Florez^{8

12

13

14}, Miriam S Udler^{8

12

13

14}

Affiliations

¹ Division of Endocrinology, Department of Medicine, NorthShore University HealthSystem/Endeavor Health, Skokie, IL, USA.
² Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, IL, US.
³ George Washington University Biostatistics Center, Washington D.C.
⁴ Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Science, Lund University. Jan Waldenströmsgata 35, Building 60, Floor 13, Skåne University Hospital, 20502, Malmö, Sweden.
⁵ Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶ University of Miami Miller School of Medicine, Miami, FL, USA.
⁷ Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
⁸ Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
⁹ Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA.
¹⁰ National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
¹¹ Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
¹² Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹³ Programs in Metabolism and Medical and Population Genetics, Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁵ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Department of Veterans Affairs Eastern Colorado Health Care System, Aurora, CO, USA.
¹⁷ Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁸ Program for Personalized Cancer Care, NorthShore University Health System, Evanston, Illinois, USA.
¹⁹ Department of Pediatrics, University of California, San Francisco, San Francisco, California.

PMID: 38758294
DOI: 10.2337/db23-0761

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.