To investigate the effects of caloric restriction and weight loss program on insulin sensitivity, acute insulin secretion and glucose effectiveness in 2 obese groups with different beta-cell function, we performed a longitudinal clinical intervention study with a 60 week weight loss program (20-25 kcal/kg ideal weight/day) in 44 obese subjects, 20 with Type 2 diabetes (OD) and 24 non-diabetic (OND). Body mass index (BMI) and metabolic parameters were determined at baseline and every 15 weeks during the intervention study. Insulin sensitivity index (Si) [10(-4) min(-1) x (mU/ml)(-1)], acute insulin response to glucose (AIRg) [pm] and glucose effectiveness (Sg) [x10(-2)/min(-1)] were assessed using the Bergman's minimal model (MINMOD). Thirty-eight subjects finished the study. BMI fell significantly in both groups: 36.2 +/- 3.7 kg/m2 to 33.5 +/- 3.4 kg/m2 (OD) and 37.6 +/- 4.2 kg/m2 to 33.3 +/- 2.9 kg/m2 (OND) (p < 0.05). Insulin sensitivity improved from 1.20 +/- 0.83 to 1.82 +/- 0.75 in the OD group (p < 0.05) and from 1.49 +/- 0.79 to 2.47 +/- 1.13 in the OND group (p < 0.001). The pancreatic beta-cell response to glucose after diet intervention was different, in OD there was a slight increase in the AIRg: 261.3 +/- 70.2 to 288.4 +/- 89.1 (p > 0.05), while a marked reduction was observed in OND subjects 1062.1 +/- 367.3 to 673.5 +/- 236.1 (p < 0.01). Glucose effectiveness did not change significantly in both groups. Weight loss significantly improved insulin sensitivity in both groups, however, the AIRg did not change in the OD group, which could represent an exhausted pancreatic beta-cell, while in the OND subjects, with initially exaggerated AIRg, weight reduction resulted in a parallel reduction in the insulin response. It is possible that this insulin release reduction by pancreatic beta-cells could theoretically avoid or delay pancreatic beta-cell exhaustion. Further studies for longer periods of time and with a larger number of subjects are needed to confirm it.