Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats

Thiazolidinediones (TZDs), a class of antidiabetic agents, are specific ago nists of peroxisome proliferator activator receptor (PPAR gamma). However, their mechanisms of action, and the in vivo target tissues that mediate ins ulin sensitization are not well understood. The aim of this study was to in vestigate the role of glucose transporters (GLUT-1 and GLUT-4) in the TZD i nsulin-sensitizer action. The effects of rosiglitazone treatment were studi ed using Zucker (fa/fa) rats after 7 days of oral dosing (3.6 mg/kg/d). Ros iglitazone lowered (approximate to 80%) basal plasma insulin levels in obes e rats and substantially corrected (approximate to 50%) insulin resistance based upon results from hyperinsulinemic euglycemic clamp studies. GLUT-4 p rotein levels were reduced (approximate to 75%) in adipose tissue of obese rats and treatment with rosiglitazone normalized them. Interestingly, GLUT- 1 protein content was increased in adipose tissue (approximate to 150%) and skeletal muscle (approximate to 50%) of obese rats and treatment with rosi glitazone increased it even more by 5.5-fold in fat and by 2.5-fold in musc le. Consistent with these results, basal (GLUT-1-mediated) transport rate o f 3-O-methyl-D-glucose into isolated epitrochlearis muscle was elevated in response to rosiglitazone. Incubation of fully differentiated 3T3-L1 adipoc ytes with the drug for 7 days increased the levels of GLUT-1 protein, but d id not affect GLUT-4 levels. In conclusion, rosiglitazone may improve insul in resistance in vivo by normalizing GLUT-4 protein content in adipose tiss ue and increasing GLUT-1 in skeletal muscle and fat. While the drug has a d irect effect on GLUT-1 protein expression in vitro without a direct effect on GLUT-4 suggests that direct and indirect effects of rosiglitazone on glu cose transporters may have an important role in improving insulin resistanc e in vivo. Copyright (C) 2001 by WB. Saunders Company.