Diabetes-associated genetic variation in TCF7L2 alters pulsatile insulin secretion in humans
Open Access
- 9 April 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
Abstract
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.Keywords
Funding Information
- US national institues of health (DK78646,DK116231)
- University of Padova Research Grant (CPDA145405)
- Mayo Clinic (UL1 TR000135)
This publication has 55 references indexed in Scilit:
- Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetesNature Genetics, 2012
- Synchronization of Pancreatic Islet Oscillations by Intrapancreatic Ganglia: A Modeling StudyBiophysical Journal, 2009
- TCF7L2 Regulates Late Events in Insulin Secretion From Pancreatic Islet β-CellsDiabetes, 2009
- Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetesJCI Insight, 2007
- TCF7L2 Polymorphisms Modulate Proinsulin Levels and β-Cell Function in a British Europid PopulationDiabetes, 2007
- Pathogenesis of Pre-DiabetesDiabetes, 2006
- TCF7L2Polymorphisms and Progression to Diabetes in the Diabetes Prevention ProgramNew England Journal of Medicine, 2006
- Evidence for temporal coupling of growth hormone, prolactin, LH and FSH pulsatility overnight during normal pubertyJournal of Endocrinology, 1991
- Analysis of serial measurements in medical research.BMJ, 1990
- Impaired Pulsatile Secretion of Insulin in Relatives of Patients with Non-Insulin-Dependent DiabetesThe New England Journal of Medicine, 1988