The role of glucose-dependent insulinotropic polypeptide (GIP) in the hyperinsulinism of morbid obesity and its correction after gastric bypass was studied in 12 morbidly obese (150 +/- 15 kg) patients. After oral glucose, significant increases in serum glucose, insulin, and GIP levels occurred both before and after gastric bypass. Compared with preoperative values, fasting concentrations and integrated incremental areas for glucose, insulin, and GIP were decreased after a 25% weight loss after gastric bypass. The hyperinsulinism of morbid obesity and its amelioration after gastric bypass may be caused by markedly elevated levels of GIP before surgery and its reduced release after bypass. Reduced release of GIP after gastric bypass may partly occur because of exclusion of ingested glucose from contact with the mucosa of the duodenum and proximal jejunum, sites with the highest concentration of GIP.