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