Although weight loss in older subjects has been shown to improve insulin sensitivity, it is unclear what effect this lifestyle intervention has on beta-cell function. To determine whether diet-induced weight loss can improve beta-cell function in older subjects, we studied 19 healthy male subjects (age, 65.4 +/- 0.9 yr; body mass index, 30.9 +/- 0.6 kg/m2; mean +/- SEM) before and after a 3-month 1200-kcal/d diet. The insulin sensitivity index (SI) was quantified using Bergman's minimal model. The acute insulin response to glucose (AIRg) and the maximal glucose-potentiated insulin response (AIRmax) were determined and then adjusted for SI (SI x AIRg and SI x AIRmax), thus providing measures of beta-cell function. Subjects demonstrated significant weight loss (95.6 +/- 2.4 to 86.1 +/- 2.5 kg; P < 0.001). Both fasting plasma glucose [97.3 +/- 1.6 to 95.1 +/- 1.3 mg/dl (5.4 +/- 0.09 to 5.3 +/- 0.07 mM); P = 0.05] and insulin [18.5 +/- 1.3 to 12.2 +/- 1.0 microU/ml (110.9 +/- 7.7 to 73.5 +/- 5.9 pM); P < 0.001] levels decreased. With weight loss, SI increased [1.59 +/- 0.24 to 2.49 +/- 0.32 x 10(-4) min(-1)/(microU/ml) (2.65 +/- 0.4 to 4.15 +/- 0.5 x 10(-5) min(-1)/pM); P < 0.001], whereas both AIRg [63.4 +/- 13.4 to 51.0 +/- 10.7 microU/ml (380 +/- 80 to 306 +/- 64 pM); P < 0.05] and AIRmax [314 +/- 31.4 to 259.9 +/- 33.4 microU/ml (1886 +/- 188 to 1560 +/- 200 pM); P < 0.05] decreased. Overall beta-cell function improved (SI x AIRg, 9.63 +/- 2.28 to 12.78 +/- 2.58 x 10(-3) min(-1), P < 0.05; and SI x AIRmax, 51.01 +/- 9.2 to 72.69 +/- 13.4 x 10(-3) min(-1), P < 0.05). Thus, the weight loss-associated improvements in both insulin sensitivity and beta-cell function may explain the beneficial effects of a lifestyle intervention on delaying the development of diabetes in older subjects.