INSULIN SENSITIZER YM268 AMELIORATES INSULIN-RESISTANCE BY NORMALIZING THE DECREASED CONTENT OF GLUT4 IN ADIPOSE-TISSUE OF OBESE ZUCKER RATS

Genetically obese Zucker rats exhibit mild hyperglycaemia and hyperins ulinaemia suggesting the existence of peripheral insulin resistance. W e have examined the effects of YM268, an analogue of thiazolidinedione , on the content and translocation of a glucose transporter (GLUT4) in epididymal adipose tissue in 11-week-old obese and lean Zucker rats. The administration of YM268 at a dose of 10 mg/kg for 2 weeks ameliora ted hyperglycaemia, hyperinsulinaemia, and impaired glucose tolerance after glucose load in obese rats. The GLUT4 content per fat pad in obe se rats was reduced to 36% of that in ban littermates. Obese rats trea ted with YM268 increased GLUT4 concentrations in their fat pads from a basal Value of 36% up to 191% of the level in lean rats. Furthermore, in adipocytes prepared from obese rats, an increase in the ratio of G LUT4 in plasma membrane to the total amount of GLUT4 (PM-GLUT4 ratio) induced by the submaximal concentration of insulin (0.3 nmol/l) was si gnificantly attenuated compared with that in lean rats. But the maximu m effect of insulin (3 nmol/l) was not attenuated. Meanwhile, YM268 ha d no significant effect on the attenuated PM-GLUT4 ratio in response t o insulin in obese rats. These data suggested that one of the mechanis ms by which YM268 improved insulin resistance in obese Zucker rats was to normalize the decreased GLUT4 content in the adipose tissue.