Lack of insulinotropic effect of endogenous and exogenous cholecystokinin in man

Intraduodenal phenylalanine administration (333 mg/min over 60 min) released endogenous cholecystokinin in healthy young subjects as demonstrated radioimmunologically and by intraduodenal bilirubin and pancreatic enzyme output. Concomitantly, there was only a small increase over basal in circulating immunoreactive-insulin and immunoreactive-C-peptide concentrations. In healthy volunteers intraduodenal infusions of saline (10 ml/min), glucose (333 mg/min) or phenylalanine (333 mg/min) were performed for 60 min when plasma glucose was clamped at approximately 8 mmol/l. Phenylalanine enhanced immunoreactive-insulin and immunoreactive-C-peptide responses three-fold more than did the same amount of glucose. Immuno-reactive gastric inhibitory polypeptide responses were small and not different after glucose and phenylalanine administration. Immunoreactive cholecystokinin was significantly stimulated to 9.4 +/- 1.4 pmol/l only by intraduodenal phenylalanine. Plasma phenylalanine concentrations increased into the supraphysiological range (approximately 1.5 mmol/l). Intravenous infusions of phenylalanine achieving plasma concentrations of 1.2 mmol/l stimulated insulin secretion at elevated plasma glucose concentrations (approximately 8 mmol/l clamp experiments), but had no effect at basal plasma glucose concentrations. A small increase in cholecystokinin also was observed. Intravenous infusions of synthetic sulphated cholecystokinin-8 leading to plasma concentrations in the upper postprandial range (8-12 pmol/l) did not augment the immunoreactive-insulin or immunoreactive-C-peptide levels during hyperglycaemic clamp experiments, in the absence or presence of elevated plasma phenylalanine concentrations. It is concluded that the augmentation of the glucose-induced insulin release by intraduodenal administration of phenylalanine cannot be related to cholecystokinin release, but rather is explained by the combined effects of elevated glucose and phenylalanine concentrations. In man, cholecystokinin does not augment insulin secretion caused by moderate hyperglycaemia, elevations of phenylalanine concentrations, or combinations thereof.