Browse by author
Lookup NU author(s): Professor Mark Walker
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
© 2017 by the American Diabetes Association. Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genomewide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.
Author(s): Wood AR, Jonsson A, Jackson AU, Wang N, Van Leewen N, Palmer ND, Kobes S, Deelen J, Boquete-Vilarino L, Paananen J, Stancakova A, Boomsma DI, De Geus EJC, Eekhoff EMW, Fritsche A, Kramer M, Nijpels G, Simonis-Bik A, Van Haeften TW, Mahajan A, Boehnke M, Bergman RN, Tuomilehto J, Collins FS, Mohlke KL, Banasik K, Groves CJ, McCarthy MI, Pearson ER, Natali A, Mari A, Buchanan TA, Taylor KD, Xiang AH, Gjesing AP, Grarup N, Eiberg H, Pedersen O, Chen Y-D, Laakso M, Norris JM, Smith U, Wagenknecht LE, Baier L, Bowden DW, Hansen T, Walker M, Watanabe RM, T'Hart LM, Hanson RL, Frayling TM
Publication type: Article
Publication status: Published
Print publication date: 01/08/2017
Online publication date: 21/07/2017
Acceptance date: 02/05/2017
ISSN (print): 0012-1797
ISSN (electronic): 1939-327X
Publisher: American Diabetes Association Inc.
PubMed id: 28490609
Altmetrics provided by Altmetric