Matsuhisa M, Shi Z Q, Wan C, Lekas M, Rodgers C D, Giacca A, Kawamori R, Vranic M
Department of Physiology, University of Toronto, Canada.
Diabetes. 1997 Feb;46(2):224-31. doi: 10.2337/diab.46.2.224.
Pioglitazone, a thiazolidinedione derivative, ameliorates hyperglycemia by augmenting peripheral glucose disposal and suppressing hepatic glucose production in diabetic animals. However, the effect of this agent on hepatic glucose uptake has not been explored. To determine this, experiments were conducted in alloxan-induced diabetic dogs with (pioglitazone group, n = 7) or without (control group, n = 5) a 10-day oral treatment with pioglitazone (1 mg x kg(-1) x day(-1)). A euglycemic-hyperinsulinemic (insulin infusion rate 25.2 pmol x kg(-1) x min(-1)) clamp was maintained by adjusting the peripheral glucose infusion rate (GIR). After a 60-min basal period (period I), portal glucose infusion (Pinf, 33.3 micromol x kg(-1) x min(-1)) was administered for 120 min (period II). This was followed by a 60-min recovery period (period III). Arterial insulin levels were kept stable in the supraphysiological range throughout the experiment (1,623 +/- 52, pioglitazone group; 1,712 +/- 52 pmol/l, C group). There was no significant difference in whole-body glucose utilization determined by [3-3H]glucose between the pioglitazone and C groups in period I (68.4 +/- 2.8 vs. 70.1 +/- 2.8 micromol x kg(-1) x min(-1), respectively) and period III (81.2 +/- 5.0 vs. 74.5 +/- 3.3 micromol x kg(-1) x min(-1), respectively). Net hepatic glucose uptake (NHGU) determined by arteriovenous difference method was approximately zero in the basal period (-0.7 +/- 1.1, pioglitazone group; 0.1 +/- 1.2 micromol x kg(-1) x min(-1), C group). In period II, hepatic glucose uptake, determined by the changes in GIR, was significantly higher in the pioglitazone group (6.5 +/- 0.6 micromol x kg(-1) x min(-1)) than in the C group (-0.4 +/- 0.6 micromol x kg(-1) x min(-1), P < 0.001). This observation was also confirmed by NHGU during portal glucose infusion (6.9 +/- 1.4 vs. 2.1 +/- 1.8 micromol x kg(-1) x min(-1), pioglitazone vs. C, respectively; P < 0.025). We conclude that pioglitazone treatment enhances hepatic glucose uptake during portal glucose loading in alloxan-induced diabetic dogs. However, in hyperinsulinemic conditions, pioglitazone does not enhance the already high peripheral glucose uptake.
吡格列酮是一种噻唑烷二酮衍生物，通过增加糖尿病动物外周葡萄糖的处置及抑制肝脏葡萄糖生成来改善高血糖。然而，该药物对肝脏葡萄糖摄取的影响尚未得到研究。为确定这一点，我们对用四氧嘧啶诱导的糖尿病犬进行了实验，一组（吡格列酮组，n = 7）给予吡格列酮（1 mg·kg⁻¹·d⁻¹）进行为期10天的口服治疗，另一组（对照组，n = 5）不进行该治疗。通过调整外周葡萄糖输注速率（GIR）维持正常血糖 - 高胰岛素血症（胰岛素输注速率为25.2 pmol·kg⁻¹·min⁻¹）钳夹状态。在60分钟的基础期（I期）后，进行120分钟的门静脉葡萄糖输注（Pinf，33.3 μmol·kg⁻¹·min⁻¹）（II期）。随后是60分钟的恢复期（III期）。在整个实验过程中，动脉胰岛素水平保持在超生理范围稳定（吡格列酮组：1,623 ± 52；对照组：1,712 ± 52 pmol/L）。在I期（分别为68.4 ± 2.8与70.1 ± 2.8 μmol·kg⁻¹·min⁻¹）和III期（分别为81.2 ± 5.0与74.5 ± 3.3 μmol·kg⁻¹·min⁻¹），吡格列酮组和对照组之间通过[3 - ³H]葡萄糖测定的全身葡萄糖利用率无显著差异。通过动静脉差值法测定的基础期肝脏净葡萄糖摄取（NHGU）在两组中均约为零（吡格列酮组：-0.7 ± 1.1；对照组：0.1 ± 1.2 μmol·kg⁻¹·min⁻¹）。在II期，通过GIR变化测定的肝脏葡萄糖摄取在吡格列酮组（6.5 ± （此处原文可能有误，推测应为0.6）μmol·kg⁻¹·min⁻¹）显著高于对照组（-0.4 ± 0.6 μmol·kg⁻¹·min⁻¹，P < 0.001）。门静脉葡萄糖输注期间的NHGU也证实了这一观察结果（吡格列酮组与对照组分别为6.9 ± 1.4与2.1 ± 1.8 μmol·kg⁻¹·min⁻¹；P < 0.025）。我们得出结论，吡格列酮治疗可增强四氧嘧啶诱导的糖尿病犬在门静脉葡萄糖负荷期间的肝脏葡萄糖摄取。然而，在高胰岛素血症条件下，吡格列酮不会增强已处于高水平的外周葡萄糖摄取。
原文中“6.5 +/- 0.6 micromol x kg(-1) x min(-1)”处第二个“+/-”后的数字0.6疑似有误，翻译时保留原文形式并做了相应推测说明。
