Effects of cholecystokinin octapeptide on the exocrine pancreas in a new rat model of type 2 diabetes

Abstract

We investigated the effects of increasing concentrations of cholecystokinin octapeptide (CCK-8) on the exocrine pancreas of a new model of type 2 diabetic rats due to the partial protection exerted by nicotinamide against the β-cytotoxic effect of streptozotocin. CCK-8, administered for 8 successive days, exerted a biphasic action on the growth of the pancreas in non-diabetic and type 2 diabetic rats; however, the latter were less sensitive to CCK-8. Similar results were obtained in vitro by measuring the uptake of 5-bromo-2′-deoxyuridine (BrdU) in cultured isolated acinar cells. This effect was completely blocked by 3 S(−)( N′-2,3-dihydro-1-methyl-2-oxo5-phenyl-1 H-1,4-benzo-diazepin-3-yl)-1 H-indole-2-carboxamide (L 364,718; a CCK 1 receptor antagonist) but not by (3 R)-3[ N′-(3-methylphenyl)ureido]-1,3-dihydro-1-methyl-5-phenyl-2 H1,4-benzo-diazepin-2-one (L 365,260; a CCK 2 receptor antagonist), suggesting a direct effect via CCK 1 receptors. Binding studies showed that these effects were mediated by a single class of low-affinity CCK 1 receptors in diabetic rats and two classes of CCK-8 binding sites (with high and low affinity) in non-diabetic rats. Thus, in our new type 2 diabetes model, the loss of sensitivity of the pancreas to CCK-8 could be attributed to the loss of CCK 1 receptors of high affinity.