Effects of D-phenylalanine- derivative hypoglycemic agent A-4166 on pancreatic α- and β-cells: Comparative study with glibenclamide

Hiroshi Hirose, Hiroshi Maruyama, Yoshiko Seto, Katsuhiko Ito, Tomonobu Fujita, Katsuaki Dan, Naoko Kanda, Takao Saruta, Ryuichi Kato

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Abstract

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 µmol/l A-4166 and 3 µmol/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 µmol/l diazoxide significantly inhibited the insulin-stimulatory effects of both 30 µmol/l A-4166 and 3 µmol/l glibenclamide (p < 0.05 and p < 0.01, respectively). However, the effects of diazoxide on glucagon secretion differed between the two groups; 30µmol/l A-4166 produced a transient increase in glucagon secretion (p < 0.05 vs. basal levels) but 3 µmol/l glibenclamide suppressed glucagon secretion further (p < 0.01 vs. without diazoxide) with concomitant administration of 100µmol/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.

Original languageEnglish
Pages (from-to)175-181
Number of pages7
JournalPharmacology
Volume50
Issue number3
DOIs
Publication statusPublished - 1995 Jan 1

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Keywords

  • Blood glucose-lowering agents
  • Glucagon
  • Insulin
  • Isolated perfused rat pancreas

ASJC Scopus subject areas

  • Pharmacology

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