Physical Activity Modifies the Effect of SNPs of the SLC2A2 (GLUT2) and ABCC8 (SUR1) Genes on the Risk of Developing Type 2 Diabetes

Single nucleotide polymorphisms (SNPs) in two genes regulating insulin secretion, SLC2A2 (encoding GLUT2) and ABCC8 (encoding SUR1) were associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study (DPS). PURPOSE: To determine whether physical activity modifies the association of SNPs in SLC2A2 and ABCC8 with the conversion to type 2 diabetes. METHODS: Post hoc analysis of a randomized controlled trial where Finnish overweight subjects with IGT (n=479) were followed between 1993 and 2000 for an average of 4.1 years. Physical activity was assessed annually with a questionnaire. RESULTS: The interaction between the rs5393, rs5394, rs5400, or rs5404 of SLC2A2, and the change in moderate-to-vigorous physical activity, categorized by tertiles, was significant (p=0.03, p=0.02, p=0.05 or p=0.02, respectively), adjusting for study group, age, gender, baseline moderate-to-vigorous physical activity and baseline levels and changes in low-intensity physical activity, body mass index and diet. The common genotype carriers had an increased risk of developing type 2 diabetes in the lower third of the change in moderate-to-vigorous physical activity and a decreased risk in the upper third, compared to the rare allele carriers. After these adjustments, the interaction between the rs2188966 or rs3758947 in ABCC8, and the change in moderate-to-vigorous physical activity was significant (p=0.02 or p=0.004, respectively). Carriers of the GG genotype for rs2188966 or rs3758947, who were in the lower third of change in moderate-to-vigorous physical activity, had a 3.7- or 6.1-fold risk of developing type 2 diabetes, respectively, compared with the A allele carriers, whereas no increased risk was seen in the middle or upper thirds. CONCLUSION: Moderate-to-vigorous physical activity may modify the risk of developing type 2 diabetes associated with genes (SLC2A2, ABCC8) regulating insulin secretion in persons with impaired glucose tolerance. Supported by grants from the Ministry of Education of Finland and the Academy of Finland.