Proglumide (gastrin and cholecystokinin receptor antagonist) inhibits insulin secretion in vitro

CCK-8 and its desulfated analog (des-CCK-8) increase insulin secretion from isolated rat pancreatic islets in the presence of 8.3 mM glucose in a concentration-dependent manner. Proglumide (DL-4-benzamido-N,N-dipropylglutaramic acid), a gastrin and cholecystokinin (CCK) receptor antagonist, inhibits the synergistic effect of CCK on insulin release in the presence of 8.3 mM glucose; its EC50 (half-maximal effective concentration) was 1.2 +/- 0.4 mM. Its effect is specific in that it does not inhibit the glucose- or GIP (glucose dependent insulinotropic peptide) induced insulin secretion to a major degree. CCK-8, des-CCK-8 and proglumide compete for binding of 125I-CCK-33 to rat pancreatic islets; the IC50 of proglumide was 0.8 mM. The affinity of proglumide is in the range of both its EC50 for inhibition of insulin secretion and its IC50 in other in vitro systems tested so far (exocrine pancreas, gall bladder, cortex). Its inhibitory effect presumably is not a gastrin antagonizing effect since gastrin does not stimulate insulin secretion. The data therefore indicate that proglumide should be monitored for diabetic effects in vivo.