Dataset Information

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

ABSTRACT: BACKGROUNDMetabolic 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 ? cell dysfunction, would be associated with changes in these insulin pulse characteristics.METHODSTwenty-nine nondiabetic subjects (age 46 ± 2, BMI 28 ± 1 kg/m2) 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.RESULTSDuring 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.CONCLUSIONDiabetes-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 ? cell health.FUNDINGThis work was funded by US NIH (DK78646, DK116231), University of Padova research grant CPDA145405, and Mayo Clinic General Clinical Research Center (UL1 TR000135).

SUBMITTER: Laurenti MC

PROVIDER: S-EPMC7205281 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Laurenti Marcello C MC Dalla Man Chiara C Varghese Ron T RT Andrews James C JC Rizza Robert A RA Matveyenko Aleksey A De Nicolao Giuseppe G Cobelli Claudio C Vella Adrian A

JCI insight 20200409 7

BACKGROUNDMetabolic 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.METHODSTwenty-nine nondiabetic subjects (age 46 ± 2, BMI 28 ± 1 kg/m2) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous for the T ...[more]

PMID: 32182220

Similar Datasets

Project description:TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African American, 7.3% Hispanic) using data pertaining to residual beta cell number; quantified islets containing insulin-positive beta cells in pancreatic tissue sections; and expressed these values as a percentage of the total number of islets from each donor (mean ± SD ICI% 9.8±21.5, range 0-92.2). Donors with a high ICI% (≥5) (n=30; 27%) vs a low ICI% (<5) (n=80; 73%) were older at onset (15.3±6.9 vs 11.1±8 years, p=0.013), had a shorter diabetes duration at donor tissue procurement (7.0±7.4 vs 18.5±14.3 years, p<0.001), a higher African ancestry score (0.2±0.3 vs 0.1±0.2, p=0.043) and a lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). After adjustment for age of onset (p=0.105), diabetes duration (p<0.001), BMI z score (p=0.145), sex (p=0.351) and African American race (p=0.053), donors with the TCF7L2 rs7903146 T allele (TC or TT, 45.5%) were 2.93 times (95% CI 1.02, 8.47) more likely to have a high ICI% than those without it (CC) (p=0.047). Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor that predisposes to type 2 diabetes, with donors in this category exhibiting less severe beta cell loss. It is possible that in these individuals the disease pathogenesis may include mechanisms associated with type 2 diabetes and thus this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment in these individuals.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets