☆ 4.7 Article

High heritability and genetic correlation of intravenous glucose- and tolbutamide-induced insulin secretion among non-diabetic family members of type 2 diabetic patients

DIABETOLOGIA (2014)

期刊

DIABETOLOGIA

卷 57, 期 6, 页码 1173-1181

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SPRINGER

DOI: 10.1007/s00125-014-3207-y

关键词

Acute insulin response; Genetic correlation; Heritability; Tolbutamide-modified frequently sampled intravenous glucose tolerance test; Type 2 diabetes

类别

Endocrinology & Metabolism

资金

Danish Medical Research Council
University of Copenhagen, an EEC grant [BMH4CT950662]
Velux Foundation
Lundbeck Foundation Centre of Applied Medical Genomics for Personalised Disease Prediction and Care (LUCAMP)
European Foundation for the Study of Diabetes (EFSD)
Danish Diabetes Association
Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen
Novo Nordisk Foundation

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摘要

Aims/hypothesis The aim of this study was to estimate the heritability of quantitative measures of glucose regulation obtained from a tolbutamide-modified frequently sampled IVGTT (t-FSIGT) and to correlate the heritability of the glucose-stimulated beta cell response to the tolbutamide-induced beta cell response. In addition, single nucleotide polymorphisms (SNPs) having an exclusive effect on either glucose- or tolbutamide-stimulated insulin release were identified. Methods Two hundred and eighty-four non-diabetic family members of patients with type 2 diabetes underwent a t-FSIGT with intravenous injection of glucose at t = 0 min and tolbutamide at t = 20 min. Measurements of plasma glucose, serum insulin and serum C-peptide were taken at 33 time points from fasting to 180 min. Insulin secretion rate, acute insulin response (AIR), disposition index (D-I) after glucose and disposition index after tolbutamide (D-IT), insulin sensitivity (S-I), glucose effectiveness (S-G) and beta cell responsiveness to glucose were calculated. A polygenic variance component model was used to estimate heritability, genetic correlations and associations. Results We found high heritabilities for acute insulin secretion subsequent to glucose stimulation (AIR(glucose) h (2) +/- SE: 0.88 +/- 0.14), but these were slightly lower after tolbutamide (AIR(tolbutamide) h (2) +/- SE: 0.69 +/- 0.14). We also estimated the heritabilities for S-I (h (2) +/- SE: 0.26 +/- 0.12), S-G (h (2) +/- SE: 0.47 +/- 0.13), D-I (h (2) +/- SE: 0.56 +/- 0.14), D-IT (h (2) +/- SE: 0.49 +/- 0.14) and beta cell responsiveness to glucose (h (2) +/- SE: 0.66 +/- 0.12). Additionally, strong genetic correlations were found between measures of beta cell response after glucose and tolbutamide stimulation, with correlation coefficients ranging from 0.77 to 0.88. Furthermore, we identified five SNPs with an exclusive effect on either glucose-stimulated (rs5215, rs1111875, rs11920090) or tolbutamide-stimulated (rs10946398, rs864745) insulin secretion. Conclusions/interpretation Our data demonstrate that both glucose- and tolbutamide-induced insulin secretions are highly heritable traits, which are largely under the control of the same genes.

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Entero-Pancreatic Hormone Secretion, Gastric Emptying, and Glucose Absorption After Frequently Sampled Meal Tests

Simon Veedfald, Jens F. Rehfeld, Gerrit van Hall, Lars B. Svendsen, Jens J. Holst

Summary: The study investigated the rapid entero-pancreatic hormone secretion after nutrient ingestion and its correlation with gastric emptying and glucose absorption. Findings showed characteristic differences in timing and amplitude of early postprandial hormone responses, emphasizing the need to consider individual variations when interpreting mean responses and designing study protocols.

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