Oral administration of SaRI 59–801 (DL-α-[dimethylaminomethyl]-2-[3-ethyl-5-methyl-4-isoxazolyl]-1H-indole-3-methanol) has been reported to decrease blood glucose in several species and to elevate plasma insulin in rats and mice. In studies with isolated rat pancreatic islets incubated 1 h with 3 mM glucose, 0.05 mM 59–801 produced a significant increase in insulin secretion, and 0.3 mM produced maximum release. 59–801 (0.3 mM) stimulated insulinrelease 4–5-fold from islets incubated with 0, 3, or 5 mM glucose but had little effect on the high rates of release obtained at 10 or 20 mM glucose. Ten millimolar mannoheptulose, which inhibits phosphorylation of glucose and blocks glucose-stimulated insulin release, had little effect on the stimulation of insulin release by 0.3 mM 59–801 from islets incubated with 3 mM glucose. Stimulation of insulin release in the absence of glucose or in the presence of 3 mM glucose plus 10 mM mannoheptulose suggests that glucose metabolism is not required for the action of 59–801. The rate of conversion of 5 mM [5–3H]-glucose to 3H2O by islets, a measure of the rate of glycolysis, was not affected by 59–801. The potency, dependency on glucose concentration, lack of inhibition by mannoheptulose, and lack of effect on glycolysis of 59–801 were similar to that of tolbutamide. However, proinsulin synthesis by islets incubated with 5.55 mM glucose was not affected by 0.5 mM 59–801, but was inhibited 72% and 67% by 0.5 mM tolbutamide and 0.1 mM glibenclamide, respectively.

This content is only available via PDF.