A TCF7L2 Single Nucleotide Polymorphism and Pancreatic b-Cell Function Post-Moderate Intensity Exercise Training

Abstract

The transcription factor 7-like 2 (TCF7L2) gene has been associated with the development of type 2 diabetes. Carriers of TCF7L2 risk variants appear to have impaired pancreatic b-cell function, possibly operating through the Wnt signaling pathway and impaired glucagon-like peptide 1 release, independent of adiposity. Aerobic exercise training has been shown to improve pancreatic b-cell function, however it is unknown if the benefits of exercise training are associated with improvements in the Wnt signaling pathway or improvements in body composition. PURPOSE: To determine if 6 months of moderate intensity exercise improves pancreatic b-cell function, and if rs7903146 genotype modifies the effect that moderate intensity exercise training has on pancreatic b-cell function, in a sample of overweight and obese post-menopausal women. METHODS: Homeostatic model assessment (HOMA)-b was used as a measure of pancreatic b-cell function and the TCF7L2 SNP rs7903146 (T/T n=26; C/T n=134; C/C n=199) was genotyped in women participating in the Dose Response to Exercise in Women trial. Participants (Age=57.2±0.3; BMI=31.6±0.2) were randomly assigned to a control group or to one of three moderate intensity exercise groups (4 kcal/kg/week, 8 KKW or 12 KKW) for 6 months. All models used log transformed HOMA-b and were adjusted for ethnicity and body mass index (BMI). RESULTS: At baseline there was no association between rs7903146 genotype and HOMA-b (T/T=102.6±7.6; C/T=117.0±5.2; C/C=130.5±5.4; p=0.26). Linear mixed models found that women in 8 and 12 KKW groups improved HOMA-b post-exercise (exercise × time, p=0.02). Within these two groups, the C/C (pre=134.5±8.1 & post=143.0±8.6, p=0.002) and C/T (pre=108.8±7.6 & post=123.5±10.5, p<0.001) genotypes improved HOMA-b post-exercise, while T/T homozygotes did not (pre=97.2±11.3 & post=100.6±12.5, p=0.78); however, no time × TCF7L2 interaction was found (p=0.70). CONCLUSION: Moderate intensity exercise training improved pancreatic b-cell function. This improvement persisted after adjusting for any changes in BMI. However, the beneficial effects of moderate intensity exercise training may not hold for overweight or obese women homozygous for the rs7903146 type 2 diabetes risk allele. Supported by NIH grants HL66262 and HL071900 & Life Fitness for equipment