EFFECTS OF TROGLITAZONE (CS-045) ON INSULIN-SECRETION IN ISOLATED RATPANCREATIC-ISLETS AND HIT CELLS - AN INSULINOTROPIC MECHANISM DISTINCT FROM GLIBENCLAMIDE

In order to elucidate the direct effects of (+/-)-5-[4-(6-hydroxy-2, 5 , 7, 8-tetramethylchroman-2-yl-methoxy) benzyl]-2,4-thiazolidinedione (Troglitazone), a newly-developed oral hypoglycaemic agent, on pancrea tic beta-cell function, in vitro investigation of isolated rat pancrea tic islets and a hamster beta-cell line (HIT cell) were performed. Tro glitazone stimulates both glucose, and glibenclamide-induced insulin r elease at a concentration of 10(-6) mol/l in these cells but, converse ly, inhibits insulin secretion at 10(-4) mol/l. Glucose uptake in HIT cells is similarly enhanced by 10(-6) mol/l Troglitazone, but is reduc ed in the presence of 10(-4) mol/l Troglitazone. However, a quantitati ve immunoblot analysis with a specific antibody for GLUT 2 glucose tra nsporter revealed no significant change in GLUT 2 protein in HIT cells with 10(-6) mol/l Troglitazone. Specific binding of [H-3]-glibenclami de to beta-cell membranes is replaced by Troglitazone in a non-competi tive manner, but 10(-6) mol/l Troglitazone failed to eliminate ATP-sen sitive K++ channel activity. These results suggest that Troglitazone h as a putative non-competitive binding site at, or in the vicinity of, the sulphonylurea receptor in rat pancreatic islets and HIT cells and that the dual effect of Troglitazone on insulin secretory capacity is mediated through the modulation of glucose transport activity, possibl y due to the modification of intrinsic activity in glucose transporter in pancreatic beta cells by this novel agent.