Pretreatment with an oral dose (45 mg/kg) of
cyproheptadine (CPH), a
drug that inhibits secretion and synthesis of
insulin. 3 hr before
alloxan (100 mg/kg, iv) protects mice from the permanent diabetes produced by
alloxan. Pretreated animals at the time of
alloxan administration were hyperglycemic. Therefore, the possibility that CPH-induced
hyperglycemia protected mice from
alloxan was investigated. This was accomplished by giving
mannoheptulose (a
glucose antagonist) or
insulin (to lower
blood glucose) after CPH and before
alloxan. These interventions eliminated CPH-induced protection from
alloxan, indicating a role for CPH-induced
hyperglycemia in the protective effect. To confirm that CPH does not protect mice from
alloxan-induced diabetes by a direct action, in vitro experiments using isolated pancreatic islets were conducted. Mouse islets were pretreated with CPH, its metabolite
desmethylcyproheptadine (DMCPH), or an equal mixture of the two and/or various concentrations of
glucose prior to an acute exposure to a toxic concentration of
alloxan.
Glucose-stimulated
insulin release was used as a measure of pancreatic beta-cell function after
alloxan exposure. CPH or DMCPH (alone or in combination) pretreatment did not provide protection against
alloxan-induced inhibition of
insulin release nor did pretreatments potentiate the protective action of
glucose against in vitro
alloxan toxicity. The results indicate that the protective action of CPH when given to mice before
alloxan is due to
drug-induced
hyperglycemia and not to a direct effect of CPH or its metabolite.