Impaired β-Cell Function in Human Aging: Response to Nicotinic Acid-Induced Insulin Resistance

Abstract

Abstract Context: Glucose tolerance declines with age and may involve impaired β-cell sensitivity to glucose and β-cell compensation for insulin resistance. Objective: We investigated β-cell sensitivity to glucose and β-cell compensation for nicotinic acid-induced insulin resistance in young (age <35 yr) people with normal glucose tolerance (NGT) and old (age >60 yr) people with NGT and impaired glucose tolerance (IGT). Design/Patients/Setting/Intervention: Fifteen young NGT, 16 old NGT, and 14 old IGT were randomized to 2-wk treatment with nicotinic acid or placebo in a double-blind, crossover study in a university medical setting. At the end of each treatment period, participants had a frequently sampled iv glucose tolerance test and ramp clamp, in which insulin secretion rates (ISR) were determined in response to a matched 5–10 mm glucose stimulus. Main Outcome Measures: Insulin sensitivity (SI), acute insulin response to iv glucose (AIRg), and disposition index (AIRg × SI, or β-cell compensation for insulin resistance) from frequently sampled iv glucose tolerance testing, and ISR area under the curve (or β-cell sensitivity to glucose) from ramp clamp were determined. Results: Progressive impairments in insulin secretion as assessed by AIRg, disposition index, and ISR area under the curve were identified in older people with NGT, with more marked defects in older people with IGT. Nicotinic acid treatment significantly reduced SI in all groups. β-Cell compensation for nicotinic acid-induced insulin resistance was incomplete in all three groups, with greater defects in the two older groups. Conclusions: Human aging is associated with impaired β-cell sensitivity to glucose and impaired β-cell compensation to insulin resistance.