Additive Effects of Genetic Variation in GCK and G6PC2 on Insulin Secretion and Fasting Glucose

  1. Xia Li1,
  2. Yu-Hsiang Shu1,
  3. Anny H. Xiang1,
  4. Enrique Trigo2,
  5. Johanna Kuusisto3,
  6. Jaana Hartiala1,4,
  7. Amy J. Swift5,
  8. Miwa Kawakubo1,
  9. Heather M. Stringham6,
  10. Lori L. Bonnycastle5,
  11. Jean M. Lawrence7,
  12. Markku Laakso3,
  13. Hooman Allayee1,4,
  14. Thomas A. Buchanan2,8 and
  15. Richard M. Watanabe1,8
  1. 1Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, California;
  2. 2Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California;
  3. 3Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland;
  4. 4Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
  5. 5Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland;
  6. 6Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan;
  7. 7Research and Evaluation, Kaiser Permanente of Southern California, Pasadena, California;
  8. 8Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California.
  1. Corresponding author: Richard M. Watanabe, rwatanab{at}usc.edu.

  1. X.L. and Y.-H.S. contributed equally to this study.

Abstract

OBJECTIVE Glucokinase (GCK) and glucose-6-phosphatase catalytic subunit 2 (G6PC2) regulate the glucose-cycling step in pancreatic β-cells and may regulate insulin secretion. GCK rs1799884 and G6PC2 rs560887 have been independently associated with fasting glucose, but their interaction on glucose-insulin relationships is not well characterized.

RESEARCH DESIGN AND METHODS We tested whether these variants are associated with diabetes-related quantitative traits in Mexican Americans from the BetaGene Study and attempted to replicate our findings in Finnish men from the METabolic Syndrome in Men (METSIM) Study.

RESULTS rs1799884 was not associated with any quantitative trait (corrected P > 0.1), whereas rs560887 was significantly associated with the oral glucose tolerance test 30-min incremental insulin response (30′ Δinsulin, corrected P = 0.021). We found no association between quantitative traits and the multiplicative interaction between rs1799884 and rs560887 (P > 0.26). However, the additive effect of these single nucleotide polymorphisms was associated with fasting glucose (corrected P = 0.03) and 30′ Δinsulin (corrected P = 0.027). This additive association was replicated in METSIM (fasting glucose, P = 3.5 × 10−10 30′ Δinsulin, P = 0.028). When we examined the relationship between fasting glucose and 30′ Δinsulin stratified by GCK and G6PC2, we noted divergent changes in these quantitative traits for GCK but parallel changes for G6PC2. We observed a similar pattern in METSIM.

CONCLUSIONS Our data suggest that variation in GCK and G6PC2 have additive effects on both fasting glucose and insulin secretion.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received February 18, 2009.
    • Accepted August 27, 2009.
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  1. Published online before print September 9, 2009, doi: 10.2337/db09-0228 Diabetes December 2009 vol. 58 no. 12 2946-2953
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