The purpose of the study was to examine the effect of short-term weight loss on glucose disposal and lipid oxidation in obese patients. Twenty-six obese patients were divided into three groups according to their degree of glucose intolerance: normal glucose tolerance = Gp I; impaired glucose tolerance without diabetes = Gp II; diabetes = Gp III. The patients submitted to an hypocaloric, high-protein diet for 8 to 45 weeks. Respiratory exchange measurements were performed by means of continuous indirect calorimetry during a 100 g, 3 h oral glucose tolerance test (OGTT) before weight loss and were repeated at the end of the weight loss period, 3 to 8 weeks after the reintroduction of a balanced isocaloric diet. Glucose tolerance, which was decreased in Gps II and III, improved after weight loss. Glucose oxidation, which was decreased in Gps II and III showed improvement after weight reduction in both Gp II (30.9 +/- 2.3 after weight loss vs 24.2 +/- 2.0 g/3 h before, P less than 0.025) and in Gp III (33.1 +/- 1.6 vs 25.8 +/- 4.1, ns). In the diabetic group (Gp III), before weight loss, a decrease in nonoxidative glucose uptake was observed, which was probably due both to a decrease in glucose storage and to the inhibition of splanchnic glucose output. After weight loss, it increased significantly from 27.7 +/- 5.2 to 56.9 +/- 2.3 g/3 h (P less than 0.001). Postabsorptive plasma insulin levels decreased in all groups following weight reduction. When exaggerated the insulin response to the glucose load fell to normal values whereas the insulin response increased in the diabetic patients in whom it was initially blunted. Lipid oxidation rates, both preload and postload, were markedly elevated before weight loss in all three groups. They were substantially reduced after weight loss. This study shows that a weight loss of 10 to 33 kg in obese patients promoted an increase in the subnormal glucose oxidation rate in Gp II as well as an improvement of the low nonoxidative glucose uptake in the diabetic group, thus improving their glucose tolerance. There was a simultaneous reduction in lipid oxidation in both groups. Furthermore, the insulin response to the glucose load, whether elevated or decreased before weight loss, tended towards normalization after weight reduction.