Diabetes-associated genetic variation in TCF7L2 alters pulsatile insulin secretion in humans
Autor: | Adrian Vella, Chiara Dalla Man, Marcello C. Laurenti, Aleksey V. Matveyenko, Giuseppe De Nicolao, James C. Andrews, Claudio Cobelli, Ron T. Varghese, Robert A. Rizza |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Pulsatile insulin medicine.medical_treatment Type 2 diabetes 03 medical and health sciences 0302 clinical medicine Endocrinology Genetic Internal medicine Diabetes mellitus Insulin-Secreting Cells Genotype Insulin Secretion Diabetes Mellitus Medicine Insulin Humans Genetic variation Allele Polymorphism Alleles Polymorphism Genetic business.industry Diabetes General Medicine Middle Aged medicine.disease Metabolism Diabetes Mellitus Type 2 Female Transcription Factor 7-Like 2 Protein Peripheral 030104 developmental biology 030220 oncology & carcinogenesis Clinical Medicine business TCF7L2 Type 2 |
Zdroj: | JCI Insight |
Popis: | 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 β 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 over time. 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 β cell health. FUNDING: This work was funded by US NIH (DK78646, DK116231), University of Padova research grant CPDA145405, and Mayo Clinic General Clinical Research Center (UL1 TR000135). |
Databáze: | OpenAIRE |
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