Susceptibility of fetal rat endocrine pancreas to the diabetogenic action of cyproheptadine

Abstract

The susceptibility of fetal endocrine pancreas to the diabetogenic action of cyproheptadine was investigated. Cyproheptadine (5 or 11 mg/kg) or water (control) was given orally once daily to pregnant rats on Days 13.5–20.5 or on Days 19.5–20.5 of gestation. Fetuses were obtained by cesarean section 24 hr after the last dose. Serum and pancreatic immunoreactive insulin and serum glucose from maternal and fetal animals were measured. Differences in maternal pancreatic insulin, serum insulin, and glucose between control and treated groups were not detected. In contrast, fetal pancreatic and serum insulin concentrations in animals exposed to 2 or 8 doses of cyproheptadine were less than 50% those of control. Drug treatment did not alter fetal pancreatic glucagon, pancreatic somatostatin, serum glucose, pancreas weight, or body weight. The drug-related depletion of fetal pancreatic insulin was reversible; the level returned to normal 3 days after cessation of the drug treatment. A similar depletion of fetal insulin was observed after 8 oral doses (11 mg/kg) of desmethylcyproheptadine, a metabolite which lacks the antiserotonin-antihistaminic properties of the parent compound. In vitro experiments showed that cyproheptadine inhibited the biosynthesis and release of insulin in fetal rat pancreas. These results indicate that cyproheptadine, when given to pregnant rats using a dose which produces no apparent effects in the maternal endocrine pancreas, causes abnormalities in the function of the insulin-secreting B cells in the fetal endocrine pancreas.