Abstract

The pancreotoxicity of cyproheptadine (CPH) in rats was characterized through measurement of proinsulin and insulin levels in the pancreas as well as plasma immunoreactive insulin (IRI) and glucose levels at various times during and after drug treatment. Daily oral doses of CPH (45 mg/kg) depleted pancreatic IRI to 25% of control within 3 days. Pancreatic IRI levels showed no further decrease during the rest of a 2-week treatment period and returned to normal levels 2 days after withdrawal of the drug. Pancreatic proinsulin levels were not significantly changed by CPH treatment, and the decrease in pancreatic IRI can be ascribed primarily to a decrease in insulin. Nonfasting hyperglycemia was evident after two doses of CPH and persisted throughout the treatment period. Plasma IRI was not significantly altered compared to control and was inappropriately low for the hyperglycemia that was produced by CPH. Daily doses of CPH given i.p. (45 mg/kg) caused a transient decrease in pancreatic IRI, but hyperglycemia did not occur. Lower i.p. doses (22.5 mg/kg/day) caused a sustained decrease in pancreatic IRI content to 45% of control after 2 weeks and hyperglycemia was evident throughout the treatment period. No changes in pasma IRI were observed as a result of drug treatment even though blood glucose was elevated. These results suggest that biochemical changes affecting insulin synthesis and/or storage are associated with previously reported CPH-induced morphologic alterations in the rat beta-cell.