Effects of short-term experimental insulin resistance and family history of diabetes on pancreatic β-cell function in nondiabetic individuals

Abstract

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 β-cell mass or function that would be revealed as an impaired insulin secretory response to short-term insulin resistance. Design: Glucose tolerance, insulin sensitivity (SI), and insulin response to iv glucose (AIRG) 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 AIRG 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 SI with NA treatment. Conclusions: Short-term β-cell compensation to NA-induced insulin resistance was incomplete and did not differ by genetic predisposition. A genetic defect controlling β-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 β-cell mass. Copyright © 2005 by The Endocrine Society.