Effects of troglitazone on dexamethasone-induced insulin resistance in rats.
Troglitazone, a thiazolidinedione derivative, has been shown to counteract 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 insulin-stimulated glucose disposal rate (Rd) by a euglycemic-hyperinsulinemic glucose clamp technique coupled with 3-3H-glucose infusion in male 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 dexamethasone plus troglitazone (LoDex + T, n = 8; HiDex + T, n = 6). Dexamethasone was injected subcutaneously for 4 days. Troglitazone was administered orally at 20 mg/d for 3 days before and for 4 days along with the dexamethasone treatment. The glucose clamp study was performed after an overnight fast in chronically catheterized conscious rats with a continuous insulin infusion of 57.4 pmol/kg/min. Basal HGP was comparable among the control (45.8 +/- 2.1 micromol/kg/min, n = 7), LoDex (47.9 +/- 4.7 micromol/kg/min), LoDex + T (46.0 +/- 2.6 micromol/kg/min), and HiDex + T (54.7 +/- 3.4 micromol/kg/min) groups. It increased about twofold in the HiDex group (80.1 +/- 5.2 micromol/kg/min, P < .05 v control). Under hyperinsulinemia, HGP was suppressed to a similar level in the control (11.3 +/- 8.8 micromol/kg/min), LoDex (10.2 +/- 8.4 micromol/kg/min), and LoDex + T (7.8 +/- 7.9 micromol/kg/min) groups. The suppressive effect of insulin on steady-state HGP during the clamp was impaired in HiDex (63.7 +/- 9.7 micromol/kg/min, P < .05) and HiDex + T (64.0 +/- 6.5 micromol/kg/min, P < .05). Rd decreased 27% in LoDex (81.5 +/- 5.8 micromol/kg/min, P < .05) and 36% in HiDex (71.3 +/- 9.4 micromol/kg/min, P < .05) compared with the controls (111.4 +/- 7.4 micromol/kg/min). Troglitazone prevented the decrease in Rd in LoDex + T (102.6 +/- 5.7 micromol/kg/min), but not in HiDex + T (67.0 +/- 6.4 micromol/kg/min). These results indicate that the development of peripheral insulin resistance was prevented by troglitazone in LoDex rats. Troglitazone may be a useful drug to treat steroid-induced diabetes.
Okumura
S
S
Third Department of Internal Medicine, Gifu University School of Medicine, Japan.
Takeda
N
N
Takami
K
K
Yoshino
K
K
Hattori
J
J
Nakashima
K
K
Sugimoto
M
M
Ishimori
M
M
Takami
R
R
Yasuda
K
K
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology*; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D005938:Glucocorticoids; D005947:Glucose / Q000096:biosynthesis; D015309:Glucose Clamp Technique; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D001786:Blood Glucose; D002839:Chromans; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D003907:Dexamethasone; D000077288:Troglitazone; D005947:Glucose