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 (DI) after glucose and disposition index after tolbutamide (DIT), insulin sensitivity (SI), glucose effectiveness (SG) 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 (AIRglucose h (2) ± SE: 0.88 ± 0.14), but these were slightly lower after tolbutamide (AIRtolbutamide h (2) ± SE: 0.69 ± 0.14). We also estimated the heritabilities for SI (h (2) ± SE: 0.26 ± 0.12), SG (h (2) ± SE: 0.47 ± 0.13), DI (h (2) ± SE: 0.56 ± 0.14), DIT (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.
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 (DI) after glucose and disposition index after tolbutamide (DIT), insulin sensitivity (SI), glucose effectiveness (SG) 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 (AIRglucose h (2) ± SE: 0.88 ± 0.14), but these were slightly lower after tolbutamide (AIRtolbutamide h (2) ± SE: 0.69 ± 0.14). We also estimated the heritabilities for SI (h (2) ± SE: 0.26 ± 0.12), SG (h (2) ± SE: 0.47 ± 0.13), DI (h (2) ± SE: 0.56 ± 0.14), DIT (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.
Authors: Dimitry A Chistiakov; V A Potapov; S A Smetanina; L N Bel'chikova; L A Suplotova; V V Nosikov Journal: Acta Diabetol Date: 2011-05-25 Impact factor: 4.280
Authors: S Barg; E Renström; P O Berggren; A Bertorello; K Bokvist; M Braun; L Eliasson; W E Holmes; M Köhler; P Rorsman; F Thévenod Journal: Proc Natl Acad Sci U S A Date: 1999-05-11 Impact factor: 11.205
Authors: Stine B Thomsen; Anette P Gjesing; Camilla N Rathcke; Claus T Ekstrøm; Hans Eiberg; Torben Hansen; Oluf Pedersen; Henrik Vestergaard Journal: PLoS One Date: 2015-07-21 Impact factor: 3.240
Authors: Theresia M Schnurr; Anette P Gjesing; Camilla H Sandholt; Anna Jonsson; Yuvaraj Mahendran; Christian T Have; Claus T Ekstrøm; Anne-Louise Bjerregaard; Soren Brage; Daniel R Witte; Marit E Jørgensen; Mette Aadahl; Betina H Thuesen; Allan Linneberg; Hans Eiberg; Oluf Pedersen; Niels Grarup; Tuomas O Kilpeläinen; Torben Hansen Journal: PLoS One Date: 2016-11-15 Impact factor: 3.240
Authors: Andrew R Wood; Anna Jonsson; Anne U Jackson; Nan Wang; Nienke van Leewen; Nicholette D Palmer; Sayuko Kobes; Joris Deelen; Lorena Boquete-Vilarino; Jussi Paananen; Alena Stančáková; Dorret I Boomsma; Eco J C de Geus; Elisabeth M W Eekhoff; Andreas Fritsche; Mark Kramer; Giel Nijpels; Annemarie Simonis-Bik; Timon W van Haeften; Anubha Mahajan; Michael Boehnke; Richard N Bergman; Jaakko Tuomilehto; Francis S Collins; Karen L Mohlke; Karina Banasik; Christopher J Groves; Mark I McCarthy; Ewan R Pearson; Andrea Natali; Andrea Mari; Thomas A Buchanan; Kent D Taylor; Anny H Xiang; Anette P Gjesing; Niels Grarup; Hans Eiberg; Oluf Pedersen; Yii-Derr Chen; Markku Laakso; Jill M Norris; Ulf Smith; Lynne E Wagenknecht; Leslie Baier; Donald W Bowden; Torben Hansen; Mark Walker; Richard M Watanabe; Leen M 't Hart; Robert L Hanson; Timothy M Frayling Journal: Diabetes Date: 2017-05-10 Impact factor: 9.461