Use of diphenylhydantoin and diazoxide to investigate insulin secretory mechanisms.
In the isolated, perfused rat pancreas, we contrasted effects of diphenylhydantoin (DPH) and diazoxide on glucose-induced biphasic insulin secretion. Either drug partially inhibited the first phase. However, DPH completely inhibited the second phase, whereas diazoxide produced inhibition, then escape and post-inhibitory overshoot. Exposure to DPH prior to glucose further inhibited the first phase, and increasing the dose had no additional effects, whereas only raising the diazoxide dose intensified inhibition of early release. DPH sequentially suppressed early response to a series of two, short, glucose pulses. In contrast, no additional effects of diazoxide were noted after its initial inhibition of the first pulse. A computer analysis was programmed from hypotheses based on these experiments. It suggests that DPH inhibits release from a labile compartment and provision of insulin to that compartment, whereas diazoxide divides the labile compartment into two sequential subcompartments. Further, the computer analysis indicates that, with diazoxide, insulin (or substances on which secretion depends) accumulates not at the final release step but at a proximal portion of the labile compartment.
D000818:Animals; D003201:Computers; D003981:Diazoxide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008954:Models, Biological; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
D007328:Insulin; D010672:Phenytoin; D005947:Glucose; D003981:Diazoxide