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The Effect of Age on Insulin Sensitivity and Insulin Secretion in First-Degree Relatives of Type 1 Diabetic Patients: A Population Analysis

Department of Bioengineering (X.M., P.V.), University of Washington, Seattle, Washington 98195; Department of Pediatrics (D.B.) and Department of Biostatistics (V.C.A.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Benaroya Research Institute (C.G.), Seattle, Washington 98101

Address all correspondence and requests for reprints to: Carla Greenbaum, M.D., Director, Diabetes Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, Washington 98101. E-mail: cjgreen{at}benaroyaresearch.org.

Context: Understanding the role of insulin resistance in type 1 diabetes may lead to new prevention strategies. Estimates of insulin resistance in first-degree relatives of those with type 1 diabetes may be obtained using the minimal model of glucose kinetics incorporating a population approach.

Objective: The objective of the study was to explore parameters contributing to glucose homeostasis in a cross-sectional study of first-degree relatives across a wide age range.

Design: Insulin sensitivity (SI) was assessed using the minimal model of glucose kinetics after an oral glucose tolerance test combined with nonlinear mixed-effects modeling. β-Cell function was measured from the insulinogenic index at 30 min (IGI₃₀). Disposition index (DI) was estimated as the product of SI and IGI₃₀.

Setting: The study was conducted at an academic center.

Subjects: Subjects included 1241 first-degree relatives (aged 2–75 yr).

Results: SI was found to be negatively correlated with age, whereas IGI₃₀ increased until young adulthood. The increase IGI₃₀ was apparently insufficient to compensate for the insulin resistance because DI decreased linearly at the rate of 0.035 (10^–2 min^–1 mmol^–1 liter per year) after young adulthood. Both IGI₃₀ and DI were significantly lower in those with vs. without autoantibodies, whereas there was no difference between these groups with respect to SI.

Conclusions: β-Cell function, adjusted for age-related insulin resistance, decreases throughout life in first-degree relatives. This deterioration may be exacerbated in the presence of autoantibodies. Oral glucose tolerance test data combined with a nonlinear mixed-effect modeling population approach may be a useful technique to evaluate SI and secretion in a population.