The oral administration of glucose results in a considerably greater increase in insulin secretion than intravenous administration. The higher insulin secretion after oral glucose is called the incretin effect and has been ascribed to stimulation of insulin secretion by gastrointestinal hormones. Recent studies in experimental animals have suggested that cholecystokinin (CCK) modulates the secretory activity of the pancreatic B-cell as well as regulating exocrine pancreatic secretion and gall bladder contraction. However, little is known about the effect of CCK on insulin release in humans. Moreover, it is not clear whether CCK is released after glucose ingestion. Until recently the ability to study CCK secretion has been hampered by the lack of a specific and sensitive assay for CCK. In this study, by using a sensitive and specific bioassay based on amylase release from isolated rat pancreatic acini, we measured plasma CCK bioactivity after oral glucose (75g) administration in normal subjects and patients with non-insulin dependent diabetes mellitus (NIDDM). In both the controls and NIDDM patients, ingestion of glucose caused a 4-to 5-fold increase in plasma CCK bioactivity prior to the increase in blood glucose and serum insulin levels. The present observatios suggest the possibility that CCK modulates insulin release in humans.