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 (mean [SD] age 51.6 [8.7] years) from a community-based prospective cohort in Korea. Participants underwent biennial 2-h 75-g oral glucose tolerance tests (OGTTs) during 14 years of follow-up, and the OGTT-derived disposition index (DI) was used as a marker for β-cell function. Genetic risk was quantified using the genome-wide polygenic risk score (PRS) and was stratified into low (1st quintile), intermediate (2nd–4th quintiles), and high (5th quintile) genetic risk. 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 the high, intermediate, and low genetic risk groups, respectively. Compared with the low genetic risk group, participants in the high 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 1-SD increase in T2D PRS, P = 1.2 × 10−4). Healthy lifestyle attenuated the rate of decline in DI across all genetic risk groups.

CONCLUSIONS

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

This article contains supplementary material online at https://doi.org/10.2337/figshare.25818472.

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