Okumura S, Takeda N, Takami K, Yoshino K, Hattori J, Nakashima K, Sugimoto M, Ishimori M, Takami R, Yasuda K
Third Department of Internal Medicine, Gifu University School of Medicine, Japan.
Metabolism. 1998 Mar;47(3):351-4. doi: 10.1016/s0026-0495(98)90270-0.
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.
曲格列酮是一种噻唑烷二酮衍生物，已被证明可对抗肥胖症和非胰岛素依赖型糖尿病（NIDDM）中的胰岛素抵抗。为了测试其对 dexamethasone 诱导的胰岛素抵抗的影响，我们通过正常血糖 - 高胰岛素血糖钳夹技术结合 3 - 3H - 葡萄糖输注，测量了雄性 Wistar 大鼠的肝葡萄糖生成（HGP）和胰岛素刺激的葡萄糖处置率（Rd）。这些大鼠分别接受低剂量 dexamethasone（[LoDex] 0.05 mg/kg/d，n = 7）、高剂量 dexamethasone（[HiDex] 0.1 mg/kg/d，n = 7）或 dexamethasone 加曲格列酮（LoDex + T，n = 8；HiDex + T，n = 6）治疗。皮下注射 dexamethasone 4 天。曲格列酮在 dexamethasone 治疗前 3 天和治疗期间 4 天每天口服 20 mg。在长期插管的清醒大鼠中，经过一夜禁食后，以 57.4 pmol/kg/min 的速度持续输注胰岛素进行葡萄糖钳夹研究。对照组（45.8 +/- 2.1 μmol/kg/min，n = 7）、LoDex 组（47.9 +/- 4.7 μmol/kg/min）、LoDex + T 组（46.0 +/- 2.6 μmol/kg/min）和 HiDex + T 组（54.7 +/- 3.4 μmol/kg/min）的基础 HGP 相当。HiDex 组（80.1 +/- 5.2 μmol/kg/min，与对照组相比 P <.05）的基础 HGP 增加了约两倍。在高胰岛素血症下，对照组（11.3 +/- 8.8 μmol/kg/min）、LoDex 组（10.2 +/- 8.4 μmol/kg/min）和 LoDex + T 组（7.8 +/- 7.9 μmol/kg/min）的 HGP 被抑制到相似水平。HiDex 组（63.7 +/- 9.7 μmol/kg/min，P <.05）和 HiDex + T 组（64.0 +/- 6.5 μmol/kg/min，P <.05）中胰岛素对钳夹期间稳态 HGP 的抑制作用受损。与对照组（111.4 +/- 7.4 μmol/kg/min）相比，LoDex 组的 Rd 降低了 27%（81.5 +/- 5.8 μmol/kg/min，P <.05），HiDex 组降低了 36%（71.3 +/- 9.4 μmol/kg/min，P <.05）。曲格列酮阻止了 LoDex + T 组 Rd 的降低（102.6 +/- 5.7 μmol/kg/min），但未阻止 HiDex + T 组 Rd 的降低（67.0 +/- 6.4 μmol/kg/min）。这些结果表明，曲格列酮可预防 LoDex 大鼠外周胰岛素抵抗的发展。曲格列酮可能是治疗类固醇诱导糖尿病的有用药物。
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