Context: Glucose tolerance declines with age and may involve impaired -cell sensitivity to glucose and -cell compensation for insulin resistance.

Objective: We investigated -cell sensitivity to glucose and -cell compensation for nicotinic acid-induced insulin resistance in young (age < 35) with normal glucose tolerance (NGT) and old (age > 60) people with NGT and impaired glucose tolerance (IGT).

Design/Patients/Setting/Intervention: 15 young NGT, 16 old NGT, and 14 old IGT were randomized to 2-week 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 (FSIGT) 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 (S_I), acute insulin response to glucose (AIRg) and disposition index (DI, AIRg x S_I, or -cell compensation for insulin resistance) from FSIGT, and ISR area under the curve (ISR AUC or -cell sensitivity to glucose) from ramp clamp were determined.

Results: Progressive impairments in insulin secretion as assessed by AIRg, DI, and ISR AUC were identified in older people with NGT, with more marked defects in older people with IGT. Nicotinic acid treatment significantly reduced insulin sensitivity in all groups. -cell compensation for nicotinic-acid induced insulin resistance was incomplete in all 3 groups, with greater defects in the 2 older groups.

Conclusions: Human aging is associated with impaired -cell sensitivity to glucose and impaired -cell compensation to insulin resistance.