Horm Metab Res 1998; 30(1): 42-49
DOI: 10.1055/s-2007-978829
Original Clinical

© Georg Thieme Verlag Stuttgart · New York

Insulin Secretion from Isolated Rat Islets Induced by the Novel Hypoglycemic Agent A-4166, a Derivative of D-Phenylalanine

K. Tsukuda1 , M. Sakurada1 , I. Niki2 , Y. Oka3 , M. Kikuchi1
  • 1Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
  • 2The Department of Pharmacology, Nagoya University, School of Medicine, Nagoya, Japan
  • 3The Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
Further Information

Publication History



Publication Date:
20 April 2007 (online)

A derivative of D-phenylalanine, A-4166, reportedly evokes a more rapid and short-lived hypoglycemic action in vivo than any of the currently available sulfonylureas. This novel oral hypoglycemic agent is structurally different from sulfonylureas. Therefore, studies were designed to elucidate the mechanisms by which A-4166 stimulates insulin secretion. Insulin release from incubated or perifused rat islets was dose-dependently stimulated by 10 to 200 µmol/l A-4166, in the presence of 2.8 mmol/l glucose. Both A-4166 and tolbutamide evoke a prompt rise in insulin secretion followed by a sustained gradually decreasing release from perfused islets in the presence of low glucose, although A-4166 appeared to be more sensitive than tolbutamide to subthreshold glucose concentration. Diaz-oxide abolished the initial release and blunted sustained release. Removing calcium from the perifusate abolished insulin release within 15 minutes. A-4166 inhibited [3H]-glibenclamide binding to HIT cell membranes and 86Rb efflux from ATP-depleted or diazoxide-treated cells. These results suggest that the insulin release induced by A-4166 is relevant to this agent occupying the tolbutamide binding sites. Therefore, one possible mechanism accounting for the more rapid and short-lived hypoglycemic action of A-4166 in vivo, as compared with tolbutamide, may involve the reported differences in the bioavailability of A-4166.