Mode of Action of a Diazoxide Analog (A025): Its Effects on Insulin Secretion

Studies of A025, an analog of diazoxide, have shown it to have hyperglycemic, but not antidiuretic, activity in rats and monkeys. A025 possesses some blood pressure-lowering activity. Catecholamine release did not appear to be involved in the hyperglycemic effect. A glucose-stimulated insulin release was inhibited in vivo by A025. Significant hyperglycemic activity was still present in adrenalectomized rats after A025 administration, whereas no hyperglycemic effect was produced by A025 in eviscerated rats. Daily administration of the compound was well tolerated by rats over a period of twelve weeks; glucose tolerance was reduced after six weeks; serum and pancreatic insulin were reduced when measured after nine weeks. Glucose tolerance was restored to normal three days after discontinuation of the drug. It is concluded that the primary mechanism ofhyper glycemia is insulin inhibition.