EFFECTS OF D-PHENYLALANINE-DERIVATIVE HYPOGLYCEMIC AGENT A-4166 ON PANCREATIC ALPHA-CELLS AND BETA-CELLS - COMPARATIVE-STUDY WITH GLIBENCLAMIDE

We have reported that N-[(trans-4-isopropyl-cyclohexyl)-carbonyl]-D-phenylalanine (A-4166) stimulates insulin secretion in animal studies, To further elucidate the mechanisms underlying the actions of this agent, we investigated the effects of A-4166 on insulin and glucagon secretion with or without diazoxide, an ATP-sensitive potassium channel opener, using isolated perfused rat pancreas preparations, and compared the results with those of glibenclamide, Both 30 mu mol/l A-4166 and 3 mu mol/l glibenclamide significantly stimulated insulin secretion and reduced glucagon secretion to similar levels at a glucose concentration of 5.6 mmol/l (p < 0.01 for both vs, basal levels), After infusion of A-4166 was stopped, insulin levels promptly returned to the basal values, while insulin levels increased further even after discontinuation of glibenclamide. Furthermore, 100 mu mol/l diazoxide significantly inhibited the insulin-stimulatory effects of both 30 mu mol/l A-4166 and 3 mu mol/l glibenclamide (p < 0.05 and p < 0.01, respectively), However, the effects of diazoxide on glucagon secretion differed between the two groups; 30 mu mol/l A-4166 produced a transient increase in glucagon secretion Cp < 0.05 vs. basal levels) but 3 mu mol/l glibenclamide suppressed glucagon secretion further (p < 0.01 vs. without diazoxide) with concomitant administration of 100 mu mol/l diazoxide. These findings suggest that A-4166 directly stimulates insulin secretion, at least in part, through mechanisms resembling those of sulfonylurea, but exerts different effect on glucagon secretion in isolated perfused rat pancreas.