INHIBITION OF INSULIN PRODUCTION BY CYPROHEPTADINE IN RINM5F RAT INSULINOMA CELLS

The clonal insulin producing cell line RINm5F was evaluated as a model for the action of cyproheptadine (CPH)-like diabetogenic compounds in the rat pancreas. Treatment with 10 muM CPH and selected structural a nalogs under culture conditions produced a progressive loss of cellula r insulin which reached 30% of control within 24 hours. Comparison of the activities of the analogs 4-diphenylmethylpiperidine (4-DPMP) and 2-diphenylmethylpiperidine (2-DPMP) to produce cellular insulin deplet ion showed that 4-DPMP was as active as CPH but 2-DPMP had no activity at the highest concentration employed (10 muM). The CPH metabolite de smethyl CPH-epoxide was five times more active than the parent compoun d in producing loss of insulin in RINm5F cells. These results are cons istent with previously published results of CPH actions in vivo. An in hibition of insulin biosynthesis with no loss of preproinsulin mRNA oc curred in RINm5F cells treated with CPH or DMCPH-epoxide. This suggest s that an effect on transcription may not be the primary action by whi ch CPH and its analogs inhibit insulin synthesis in vivo.