Effect of a Cholecystokinin Antagonist on Meal-Stimulated Insulin and Pancreatic Polypeptide Release in Humans*

Abstract

A cholecystokinin (CCK) receptor antagonist, loxiglumide, was used to investigate the potential regulating role of CCK in the entero-insular axis in humans. Ingestion of a mixed liquid meal stimulated plasma CCK, insulin, and pancreatic polypeptide (PP) release in the control experiment. With iv loxiglumide (22 mumol/kg.h), mean plasma insulin and glucose levels did not differ between placebo and loxiglumide treatment. The area under the plasma concentration for PP was reduced to 6,060 +/- 1,706 (P less than 0.05) compared to that during placebo treatment (12,266 +/- 4,748). Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum. However, PP secretion in response to the intraduodenal meal or amino acid mixture was abolished after loxiglumide (P less than 0.05). Intravenous administration of the 10-amino acid mixture stimulated insulin from a mean basal level of 7 +/- 3 microU/mL to a peak level of 16 +/- 4 microU/mL. Infusion of a CCK octapeptide (CCK-8) at 8.6 pmol/kg.h, which produced a plasma concentration of 3.3 pmol/L, which is within the postprandial range, augmented amino acid-stimulated insulin and PP output (P less than 0.05). When CCK-8 was infused with loxiglumide, the insulin and PP responses were similar to the values found with loxiglumide alone. We conclude that CCK receptor blockade with iv loxiglumide does not affect postprandial insulin secretion. CCK is, therefore, not a major incretin. However, it is involved in the postprandial PP response, especially during the intestinal phase stimulation. These data suggest that CCK has a role in the human enteroinsular axis.