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Effects of Short-Term Experimental Insulin Resistance and Family History of Diabetes on Pancreatic ß-Cell Function in Nondiabetic Individuals

Medicine and Research Services, Central Arkansas Veterans Healthcare System (N.R., T.H., S.C.E.), Little Rock, Arkansas 72205; Division of Endocrinology, Department of Medicine (N.R., T.H., S.C.E.), and Department of Biostatistics (H.J.S.), University of Arkansas for Medical Sciences Colleges of Public Health and Medicine, Little Rock, Arkansas 72205; and Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Healthcare System and University of Washington School of Medicine (S.E.K.), Seattle, Washington 98108

Address all correspondence and requests for reprints to: Dr. Steven C. Elbein, Endocrinology 111J-1/LR, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205. E-mail: elbeinstevenc{at}uams.edu.

Context: Normal glucose homeostasis is maintained despite reductions in insulin sensitivity by increasing insulin secretion. This ability to compensate for reduced insulin sensitivity is highly heritable, but the mechanisms for this compensation or its failure in type 2 diabetes (T2DM) are unknown.

Objective: The objective of this study was to test whether individuals with a family history of T2DM have a fixed decrease in ß-cell mass or function that would be revealed as an impaired insulin secretory response to short-term insulin resistance.

Design: Glucose tolerance, insulin sensitivity (S_I), and insulin response to iv glucose (AIR_G) were compared in nondiabetic individuals with and without a family history of diabetes before and after nicotinic acid (NA) treatment.

Setting: This study was performed at the Ambulatory General Clinical Research Center.

Subjects: Healthy, nonobese, nondiabetic individuals with or without a family history of T2DM were studied.

Interventions: Oral NA was given, with a final dose of 2 g/d, for at least 7 d.

Main Outcome Measure: The main outcome measure was the disposition index (insulin sensitivity x insulin response) in response to NA.

Results: Postchallenge plasma glucose levels rose during NA therapy regardless of family history. Neither group adequately increased their AIR_G to maintain the disposition index. Family members did not differ from controls at baseline or after NA treatment for any outcome measure, but only 28 of 52 subjects experienced a 25% or greater fall in S_I with NA treatment.

Conclusions: Short-term ß-cell compensation to NA-induced insulin resistance was incomplete and did not differ by genetic predisposition. A genetic defect controlling ß-cell growth in response to chronic insulin resistance better explains differences in the ability to compensate for insulin resistance than an inherited, fixed defect in ß-cell mass.

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