The aim of the study was to estimate insulin sensitivity (SI), insulin secretion, and glucose effectiveness (SG) in 10 subjects with normal glucose tolerance (eight men and two women) with a family history of non-insulin-dependent diabetes mellitus (NIDDM offspring). Ten glucose-tolerant subjects (eight men and two women) without a family history of NIDDM served as control subjects. All subjects were Japanese. They underwent a modified frequently sampled intravenous glucose tolerance test (FSIGT): glucose (300 mg/kg body weight) was administered, and insulin (20 mU/kg over 5 minutes) was infused from 20 to 25 minutes after glucose. SI and SG were estimated by Bergman's minimal-model method. No significant difference was observed in body mass index (22.6 +/- 1.5 v 21.5 +/- 0.6 kg/m2) and fasting glucose (5.1 +/- 0.1 v 5.2 +/- 0.1 mol/L) and insulin (40.7 +/- 6.3 v 42.6 +/- 6.7 pmol/L). SI was not different between the two groups (0.83 +/- 0.11 v 0.94 +/- 0.15 x 10(-1).min-1.pmol/ L-1, P > .05). The acute insulin response to glucose (AIRglucose) estimated by intravenous glucose tolerance testing was significantly lower in the offspring than in the normal controls (2,139 +/- 265 v 3,438 +/- 318 pmol/L.min, P < .05). The glucose disappearance rate (KG) and SG were significantly diminished in the offspring versus normal controls (KG, 1.50 +/- 0.22 v 2.10 +/- 0.15 min-1, P < .05; SG, 0.016 +/- 0.003 v 0.023 +/- 0.002 min-1, P < .05). Thus, glucose-tolerant Japanese NIDDM offspring with normal insulin sensitivity are characterized by a reduced AIRglucose and diminished SG. This is the first report that glucose resistance but not insulin resistance already exists in glucose-tolerant Japanese NIDDM offspring.