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A genome-wide association study of IVGTT-based measures of first-phase insulin secretion refines the underlying physiology of type 2 diabetes variants

Lookup NU author(s): Professor Mark Walker

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Abstract

© 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.

Publication metadata

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

Journal: Diabetes

Year: 2017

Volume: 66

Issue: 8

Pages: 2296-2309

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.

URL: https://doi.org/10.2337/db16-1452

DOI: 10.2337/db16-1452

PubMed id: 28490609

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