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Progressive Loss of β-Cell Function Leads to Worsening Glucose Tolerance in First-Degree Relatives of Subjects With Type 2 Diabetes

  1. Miriam Cnop, MD, PHD1,
  2. Josep Vidal, MD, PHD1,
  3. Rebecca L. Hull, PHD1,
  4. Kristina M. Utzschneider, MD1,
  5. Darcy B. Carr, MD2,
  6. Todd Schraw, PHD3,
  7. Philipp E. Scherer, PHD3,
  8. Edward J. Boyko, MD4,
  9. Wilfred Y. Fujimoto, MD1 and
  10. Steven E. Kahn, MB, CHB1
  1. 1Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington
  2. 2Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
  3. 3Departments of Cell Biology and Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, New York
  4. 4Division of General Internal Medicine, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington
  1. Address correspondence and reprint requests to Steven E. Kahn, MB, ChB, VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA 98108. E-mail: skahn{at}u.washington.edu

Abstract

OBJECTIVE—The relative roles of insulin resistance and β-cell dysfunction in the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes are debated. First-degree relatives of individuals with type 2 diabetes are at increased risk of developing hyperglycemia.

RESEARCH DESIGN AND METHODS—We evaluated the evolution of insulin sensitivity, β-cell function, glucose effectiveness, and glucose tolerance over 7 years in 33 nondiabetic, first-degree relatives of type 2 diabetic individuals using frequently sampled tolbutamide-modified intravenous and oral glucose tolerance tests.

RESULTS—Subjects gained weight, and their waist circumference increased (P < 0.05). Insulin sensitivity, the acute insulin response to glucose, and glucose effectiveness did not change significantly. However, when we accounted for the modulating effect of insulin sensitivity on insulin release, β-cell function determined as the disposition index decreased by 22% (P < 0.05). This decrease was associated with declines in intravenous and oral glucose tolerance (P < 0.05 and P < 0.001, respectively). Of the subjects with normal glucose tolerance at the first assessment, we compared those who progressed to IGT with those who did not. The disposition index was 50% lower in the progressors than in the nonprogressors at follow-up (P < 0.05).

CONCLUSIONS—The decline in glucose tolerance over time in first-degree relatives of type 2 diabetic individuals is strongly related to the loss of β-cell function. Thus, early interventions to slow the decline in β-cell function should be considered in high-risk individuals.

Footnotes

  • M.C. is currently affiliated with the Laboratory of Experimental Medicine and Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium; and J.V. is currently affiliated with the Obesity Unit, Department of Endocrinology, Hospital Clínic, Barcelona, Spain.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    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.

    • Accepted November 28, 2006.
    • Received August 31, 2006.
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