This study was designed to explore the short-term effect of glipizide on insulin secretion and metabolism. Plasma insulin and C-peptide levels in the fasting state and after a 100-g oral glucose load were measured in 17 obese newly diagnosed type II (non-insulin-dependent) diabetic subjects before and after 1 mo of treatment with glipizide (15 mg/day). Plasma glucose levels decreased significantly after treatment with glipizide. Plasma insulin and C-peptide concentrations in the fasting state did not change after glipizide treatment. Also, postglucose plasma insulin levels did not change after glipizide, whereas postglucose plasma C-peptide concentrations significantly increased. A significant relationship was found between the increase in C-peptide plasma levels and the decrease in glycemic profile after glucose load following glipizide treatment. The relation between plasma C-peptide and insulin incremental areas after the oral glucose load significantly increased after treatment. These results suggest that in obese type II diabetic patients, 1 mo of treatment with glipizide potentiates the beta-cell response to oral glucose load and increases insulin metabolism, probably within the liver.