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

¹ Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington
² Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
³ Departments of Cell Biology and Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, New York
⁴ Division of General Internal Medicine, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington

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

OBJECTIVE—The relative roles of insulin resistance and ß-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, ß-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, ß-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 ß-cell function. Thus, early interventions to slow the decline in ß-cell function should be considered in high-risk individuals.

Abbreviations: AIR_g, acute insulin response to glucose • AUC_G, area under the curve for glucose • DI, disposition index • FSIGT, frequently sampled intravenous glucose tolerance test • GENNID, Genetics of Non-Insulin Dependent Diabetes Mellitus • GEZI, glucose effectiveness at zero insulin • IGT, impaired glucose tolerance • NGT, normal glucose tolerance • OGTT, oral glucose tolerance test

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