Although cholecystokinin (CCK) is a potent GI hormone, little is know about its physiology and pathology. With the recent development of sensitive and specific assays for measuring fasting and postprandial plasma levels of CCK, the major stimuli for CCK secretion and the physiologic role of CCK in target tissues can now be determined. This proposed research will study the regulation of CCK secretion by neurotransmitters and hormones and the action of CCK on target tissues. CCK secretion will be correlated with the actions of CCK on gastric emptying, gall bladder contraction, and insulin release in normals and patients with various diseases. Stimulation of CCK secretion by cephalic, gastric, and intestinal mechanisms will be studied and regulation of CCK release by neurohormonal agents will be evaluated. In obesity, the contribution of CCK to altered gasteric emptying, gall bladder contraction, gallstone development, and glucose metabolism will also be studied. Whether CCK secretion and gallbladder contraction are normal in patients with gallstone disease will be investigated. Since CCK potentiates insulin secretion, the role of CCK on insulin secretion and glucose tolerance will be evaluated in normal subjects and in patients with non-insulin dependent diabetes mellitus. In rat models, the dietary and pharmacologic regulation of CCK secretion and CCK synthesis will be studied. The effects of cholinergic, adrenergic, and dopaminergic factors as well as those of the gut hormones bombesin, somatostatin and PYY on CCK release will be determined. The relationship of CCK secretion to intestinal CCK biosynthesis will be evaluated by measuring plasma CCK, intestinal CCK content and CCK mRNA levels. These studies in humans and rats should provide insight into the role of CCK in health and diseases.