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

Authors

• Liana K. Billings, Division of Endocrinology, Department of Medicine, NorthShore University HealthSystem/Endeavor Health, Skokie, IL, USA.
• Kathleen A. Jablonski, George Washington University Biostatistics Center, Washington D.C.
• Qing Pan, George Washington University Biostatistics Center, Washington D.C.
• Paul W. Franks, 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.
• Ronald B. Goldberg, University of Miami Miller School of Medicine, Miami, FL, USA.
• Marie-France Hivert, Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
• Steven E. Kahn, Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA.
• William C. Knowler, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ.
• Christine G. Lee, Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
• Jordi Merino, Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
• Alicia Huerta-Chagoya, Center for Genomic Medicine and Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
• Josep M. Mercader, Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
• Sridharan Raghavan, Department of Veterans Affairs Eastern Colorado Health Care System, Aurora, CO, USA.
• Zhuqing Shi, Program for Personalized Cancer Care, NorthShore University Health System, Evanston, Illinois, USA.
• Shylaja Srinivasan, Department of Pediatrics, University of California, San Francisco, San Francisco, California.
• Jianfeng Xu, Program for Personalized Cancer Care, NorthShore University Health System, Evanston, Illinois, USA.
• Jose C. Florez, Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
• Miriam S. Udler, Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.

Document Type

Journal Article

Publication Date

5-17-2024

Journal

Diabetes

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.

APA Citation

Billings, Liana K.; Jablonski, Kathleen A.; Pan, Qing; Franks, Paul W.; Goldberg, Ronald B.; Hivert, Marie-France; Kahn, Steven E.; Knowler, William C.; Lee, Christine G.; Merino, Jordi; Huerta-Chagoya, Alicia; Mercader, Josep M.; Raghavan, Sridharan; Shi, Zhuqing; Srinivasan, Shylaja; Xu, Jianfeng; Florez, Jose C.; and Udler, Miriam S., "Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes" (2024). GW Authored Works. Paper 4916.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4916

Department

Biostatistics and Bioinformatics