Diabetes-associated genetic variation in TCF7L2 alters pulsatile insulin secretion in humans

BACKGROUND. Metabolic disorders such as type 2 diabetes have been associated with a decrease in insulin pulse frequency and amplitude. We hypothesized that the T allele at rs7903146 in TCF7L2, previously associated with beta cell dysfunction, would be associated with changes in these insulin pulse characteristics. METHODS. Twenty-nine nondiabetic subjects (age 46 +/- 2, BMI 28 +/- 1 kg/m(2)) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous for the T allele. Deconvolution of peripheral C-peptide concentrations allowed the reconstruction of portal insulin secretion overtime. These data were used for subsequent analyses. Pulse orderliness was assessed by approximate entropy (ApEn), and the dispersion of insulin pulses was measured by a frequency dispersion index (FDI) after a Fast Fourier Transform (FFT) of individual insulin secretion rates. RESULTS. During fasting conditions, the CC genotype group exhibited decreased pulse disorderliness compared with the TT genotype group (1.10 +/- 0.03 vs. 1.19 +/- 0.04, P = 0.03). FDI decreased in response to hyperglycemia in the CC genotype group, perhaps reflecting less entrainment of insulin secretion during fasting. CONCLUSION. Diabetes-associated variation in TCF7L2 is associated with decreased orderliness and pulse dispersion, unchanged by hyperglycemia. Quantification of ApEn and FDI could represent novel markers of beta cell health.