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Higher Genetic Risk for Type 2 Diabetes Is Associated with a Faster Decline of Beta Cell Function in an East Asian Population

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posted on 2024-06-03, 16:09 authored by Hyunsuk Lee, Jaewon Choi, Jong-Il Kim, Richard M. Watanabe, Nam H Cho, Kyong Soo Park, Soo Heon Kwak

Objective: While most genetic variants of type 2 diabetes (T2D) are suggested to be associated with β-cell dysfunction cross-sectionally, their association with the longitudinal change of β-cell function remains largely unknown.

Research Design and Methods: We analyzed data from 6,311 participants without T2D at baseline (age: mean±SD 51.6±8.7) from a community-based prospective cohort in Korea. Participants underwent biennial 2h 75g oral glucose tolerance test (OGTT) during 14 years of follow-up and OGTT-derived disposition index (DI) was used as a marker for β-cell function. Genetic risk was quantified using genome-wide polygenic risk score (PRS) and was stratified into low (1st quintile), intermediate (2nd to 4th) and high genetic risk (5th). Lifestyle was assessed according to Life’s Essential 8.

Results: During a mean follow-up of 10.9 years, 374 (29.6%), 851 (22.5%) and 188 (14.9%) participants developed T2D in high, intermediate, and low genetic risk group, respectively. Participants in high genetic risk group, compared to low genetic risk group, had a 25% lower DI at baseline. Furthermore, in longitudinal analysis we observed a 1.83-fold faster decline in log2-transformed DI per year (-0.034 vs -0.019, P=2.1×10-3; per SD increase in T2D PRS, P=1.2×10-4). Healthy lifestyle attenuated the rate of decline in DI across all genetic risk group.

Conclusion: Individuals with a higher genetic risk for T2D exhibited not only a lower OGTT-derived β-cell function at baseline but notably a more rapid decline during follow-up. This information could be used to enable a focused precision prevention with lifestyle intervention.

Funding

This work was supported by the National Research Foundation of Korea grant funded by the Korean Ministry of Science and ICT (RS-2023-00262002) (grant to S.H.K.), by the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant to H.L.), by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1A6A1A03047972) (grant to H.L. and J.K.) and by the Ministry of Food and Drug Safety grant (23212MFDS202) in 2023 (grant to S.H.K.). H.L., J.C. and S.H.K. are supported by NHGRI, grant FAIN# U01HG011723. R.M.W. was partly supported by NIH grant DK-105517.

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