EFFECTS OF TROGLITAZONE ON DEXAMETHASONE-INDUCED INSULIN-RESISTANCE IN RATS

Troglitazone, a thiazolidinedione derivative, has been shown to counte ract insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NIDDM). To test its effects on dexamethasone-induced insulin resistance, we measured hepatic glucose production (HGP) and the insu lin-stimulated glucose disposal rate (Rd) by a euglycemic-hyperinsulin emic glucose clamp technique coupled with 3-H-3-glucose infusion in ma le Wistar rats treated with low-dose dexamethasone ([LoDex] 0.05 mg/kg /d, n = 7), high-dose dexamethasone ([HiDex] 0.1 mg/kg/d, n = 7), or d examethasone plus troglitazone (LoDex + T, n = 8; HiDex + Tn = 6). Dex amethasone was injected subcutaneously for 4 days. Troglitazone was ad ministered orally at 20 mg/d for 3 days before and for 4 days along wi th the dexamethasone treatment. The glucose clamp study was performed after an overnight fast in chronically catheterized conscious rats wit h a continuous insulin infusion of 57.4 pmol/kg/min. Basal HGP was com parable among the control (45.8 +/- 2.1 mu mol/kg/min, n = 7), LoDex ( 47.9 +/- 4.7 mu mol/kg/min), LoDex + T (46.0 +/- 2.6 mu mol/kg/min), a nd HiDex+T (54.7 +/- 3.4 mu mol/kg/min) groups. It increased about two fold in the HiDex group (80.1 +/- 5.2 mu mol/kg/min, P < .05 v control ). Under hyperinsulinemia, HGP was suppressed to a similar level in th e control (11.3 +/- 8.8 mu mol/kg/min), LoDex (10.2 +/- 8.4 mu mol/kg/ min), and LoDex+T (7.8 +/- 7.9 mu mol/kg/min) groups. The suppressive effect of insulin on steady-state HGP during the clamp was impaired in HiDex (63.7 +/- 9.7 mu mol/kg/min, P < .05) and HiDex+T (64.0 +/- 6.5 mu mol/kg/min, P < .05). Rd decreased 27% in LoDex (81.5 +/- 5.8 mu m ol/kg/min, P < .05) and 36% in HiDex (71.3 +/- 9.4 mu mol/kg/min, P < .05) compared with the controls (111.4 +/- 7.4 mu mol/kg/min). Troglit azone prevented the decrease in Rd in LoDex+T (102.6 +/- 5.7 mu mol/kg /min), but not in HiDex+T (67.0 +/- 6.4 mu mol/kg/min). These results indicate that the development of peripheral insulin resistance was pre vented by troglitazone in LoDex rats. Troglitazone may be a useful dru g to treat steroid-induced diabetes. Copyright (C) 1998 by W.B. Saunde rs Company.