Surgical alterations of the pancreas affect peripheral glucose, insulin, and glucagon levels with accompanying changes in carbohydrate metabolism. The sulfonylurea glipizide has been used to treat insulin-deficient states; however, its mechanism is not completely known. We hypothesized that glipizide would correct postoperative changes in glucose handling in a way that would allow more complete understanding of the drug's action. Two surgical groups (Group 1:80 percent proximal pancreatectomy; Group 2: proximal pancreatectomy plus splenocaval diversion) were compared with a healthy control group (Group 3). We have concluded that glipizide may have affected basal insulin sensitivity in the control group and Group 2 animals without affecting insulin secretion in response to oral or intravenous glucose stimulation. Glipizide does not correct the alterations in glucose handling or insulin secretion after reduction in beta-cell mass.