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Variant near ADAMTS9 Known to Associate with Type 2 Diabetes Is Related to Insulin Resistance in Offspring of Type 2 Diabetes Patients—EUGENE2 Study

Author

Listed:
  • Trine Welløv Boesgaard
  • Anette Prior Gjesing
  • Niels Grarup
  • Jarno Rutanen
  • Per-Anders Jansson
  • Marta Letizia Hribal
  • Giorgio Sesti
  • Andreas Fritsche
  • Norbert Stefan
  • Harald Staiger
  • Hans Häring
  • Ulf Smith
  • Markku Laakso
  • Oluf Pedersen
  • Torben Hansen
  • for the EUGENE2 Consortium

Abstract

Backround: A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity. Methodology/Results: Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2nd phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits. Conclusion: The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.

Suggested Citation

  • Trine Welløv Boesgaard & Anette Prior Gjesing & Niels Grarup & Jarno Rutanen & Per-Anders Jansson & Marta Letizia Hribal & Giorgio Sesti & Andreas Fritsche & Norbert Stefan & Harald Staiger & Hans Här, 2009. "Variant near ADAMTS9 Known to Associate with Type 2 Diabetes Is Related to Insulin Resistance in Offspring of Type 2 Diabetes Patients—EUGENE2 Study," PLOS ONE, Public Library of Science, vol. 4(9), pages 1-7, September.
    • Handle: RePEc:plo:pone00:0007236
    DOI: 10.1371/journal.pone.0007236
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    References listed on IDEAS

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    1. Robert Sladek & Ghislain Rocheleau & Johan Rung & Christian Dina & Lishuang Shen & David Serre & Philippe Boutin & Daniel Vincent & Alexandre Belisle & Samy Hadjadj & Beverley Balkau & Barbara Heude &, 2007. "A genome-wide association study identifies novel risk loci for type 2 diabetes," Nature, Nature, vol. 445(7130), pages 881-885, February.
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