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Brief Genetics Report

The Gly972Arg Polymorphism in the Insulin Receptor Substrate-1 Gene Contributes to the Variation in insulin Secretion in Normal Glucose-Tolerant Humans

  1. Michael Stumvoll,
  2. Andreas Fritsche,
  3. Annette Volk,
  4. Norbert Stefan,
  5. Alexander Madaus,
  6. Elke Maerker,
  7. Anna Teigeler,
  8. Matthias Koch,
  9. Fausto Machicao and
  10. Hans Häring
  1. Medical Clinic, Department of Endocrinology, Metabolism, and Pathobiochemistry, University of Tübingen, Germany
    Diabetes 2001 Apr; 50(4): 882-885. https://doi.org/10.2337/diabetes.50.4.882
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    Abstract

    The Gly972Arg polymorphism in the insulin receptor substrate (IRS)-1 was found in some studies to have a higher prevalence in type 2 diabetic subjects than in control subjects. Previously, transfection of IRS-1 with this polymorphism into insulin-secreting cells resulted in a marked reduction of glucose-stimulated insulin secretion compared with the wild-type transfected cells. In the present study, we compared insulin secretion in well-matched normal glucose-tolerant subjects with and without this polymorphism. Several validated indexes of β-cell function from the oral glucose tolerance test were significantly lower in X/Arg (n = 31) compared with Gly/Gly (n = 181) (P between 0.002 and 0.05), whereas insulin sensitivity (measured with a euglycemic clamp) was not different. During a modified hyperglycemic clamp, insulin secretion rates were significantly lower in Gly/Arg (n = 8) compared with Gly/Gly (n = 36) during the first phase (1,711 ± 142 vs. 3,014 ± 328 pmol/min, P = 0.05) and after maximal stimulation with arginine (5,340 ± 639 vs. 9,075 ± 722 pmol/min, P = 0.03). In summary, our results suggest that the Gly972Arg polymorphism in IRS-1 is associated with decreased insulin secretion in response to glucose but not with insulin sensitivity. It is possible that this polymorphism causes insulin resistance at the level of the β-cell and contributes to the polygenic etiology of type 2 diabetes.

    • CIR30, corrected insulin response after 30 min
    • CPAUC, C-peptide area under the curve
    • GAUC, glucose area under the curve
    • GLP-1, glucagon-like peptide 1
    • IAUC, insulin area under the curve, IRS, insulin receptor substrate
    • ISI, insulin sensitivity index
    • IVGTT, intravenous glucose tolerance test
    • MCR, metabolic clearance rate of glucose
    • OGTT, oral glucose tolerance tests
    • PI3-K, phosphatidylinositol 3-kinase

    Footnotes

    • Address correspondence and reprint requests to Dr. Michael Stumvoll, Medizinische Universitätsklinik, Otfried-Mühller-Str. 10, D-72076 Tübingen, Germany. Email: Michael.Stumvoll{at}med.uni-tuebingen.de.

      Received for publication 11 July 2000 and accepted in revised form 20 December 2000.

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    The Gly972Arg Polymorphism in the Insulin Receptor Substrate-1 Gene Contributes to the Variation in insulin Secretion in Normal Glucose-Tolerant Humans
    Michael Stumvoll, Andreas Fritsche, Annette Volk, Norbert Stefan, Alexander Madaus, Elke Maerker, Anna Teigeler, Matthias Koch, Fausto Machicao, Hans Häring
    Diabetes Apr 2001, 50 (4) 882-885; DOI: 10.2337/diabetes.50.4.882

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    The Gly972Arg Polymorphism in the Insulin Receptor Substrate-1 Gene Contributes to the Variation in insulin Secretion in Normal Glucose-Tolerant Humans
    Michael Stumvoll, Andreas Fritsche, Annette Volk, Norbert Stefan, Alexander Madaus, Elke Maerker, Anna Teigeler, Matthias Koch, Fausto Machicao, Hans Häring
    Diabetes Apr 2001, 50 (4) 882-885; DOI: 10.2337/diabetes.50.4.882
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