The attempt has been made to identity the lowest dose of glipizide, a second generation sulphonylurea, capable of improving glucose tolerance in overweight and obese subjects with various degrees of glucose tolerance. Thirty one obese subjects, 12 with non insulin dependent diabetes mellitus (NIDDM), 9 with impaired glucose tolerance (IGT) and 10 with normal glucose tolerance (NGT) each underwent four OGTTS (75 g), at 1 week intervals, after administration in random order of placebo or glipizide 0.5, 1.0 or 2.5 mg 30 min before glucose. Glucose tolerance in all groups was progressively improved by the increasing doses of glipizide and was normalized by 1.0 mg glipizide in impaired glucose tolerance (IGT) and by 2.5 mg glipizide in NIDDM. Insulin release was not significantly affected by glipizide in the three groups of subjects. The data indicate that it is possible, at least in acute experiments, to improve glucose tolerance in overweight and obese subjects with IGT, with NGT and with NIDDM, with doses of glipizide that do not affect insulin release.