Miles P D, Higo K, Romeo O M, Lee M K, Rafaat K, Olefsky J M
Department of Surgery, University of California, San Diego, USA.
Diabetes. 1998 Mar;47(3):395-400. doi: 10.2337/diabetes.47.3.395.
Hyperglycemia can lead directly to a secondary state of insulin resistance or can worsen a preexisting insulin-resistant state. Troglitazone is an orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and NIDDM subjects. To determine whether this drug could prevent the development of hyperglycemia-induced insulin resistance and to investigate the mechanism by which this might occur, we studied troglitazone's effect on insulin action in rats made hyperglycemic or infused with glucosamine. Normal male SD rats were fed regular powdered diet with or without troglitazone as a food admixture (0.2%). After 2 weeks, rats were made hyperglycemic with glucose (52 mg x kg(-1) x min[-1]) and somatostatin (0.8 microg x kg(-1) x min[-1]) infusion or were infused with glucosamine (6.5 mg x kg(-1) x min[-1]) for 6.5 h. In vivo insulin action was measured by the hyperinsulinemic-euglycemic clamp technique at a submaximal (24 pmol x kg(-1) x min[-1]) or maximal (240 pmol x kg(-1) x min[-1]) insulin infusion rate. The infusion of glucose and somatostatin caused a pronounced rise in the plasma glucose concentration (19.8 +/- 0.6 mmol/l) compared with saline-infused animals (8.0 +/- 0.2 mmol/l; P < 0.001). Hyperglycemia resulted in insulin resistance, as evidenced by a marked reduction in the submaximal glucose disposal rate (GDR) (78 +/- 7 vs. 135 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) and maximal GDR (141 +/- 9 vs. 237 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) compared with the control group. Troglitazone treatment largely prevented the hyperglycemia-induced decline in submaximal (116 +/- 7 micromol x kg(-1) x min[-1]) and maximal GDR (209 +/- 9 micromol x kg(-1) x min(-1); P < 0.05). Glucosamine infusion also resulted in a marked reduction in the submaximal GDR (85 +/- 3 vs. 135 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) and maximal GDR (137 +/- 14 vs. 237 +/- 6 micromol x kg(-1) x min(-1); P < 0.01) compared with the control group. In contrast to the results in the hyperglycemic animals, troglitazone treatment had no effect on glucosamine-induced insulin resistance. In summary, 1) in normal rats, experimental hyperglycemia, as well as glucosamine infusion, led to a marked state of peripheral and hepatic insulin resistance; 2) troglitazone treatment prevented the hyperglycemia-induced, but not the glucosamine-induced, insulin resistance; and 3) either troglitazone acts at one or more sites proximal to the entry of glucosamine into the hexosamine pathway, or the increased flux of glucose-derived products through the hexosamine pathway is not a major mechanism for the hyperglycemia-induced defect in insulin action in these animals.
高血糖可直接导致继发性胰岛素抵抗状态，或使已存在的胰岛素抵抗状态恶化。曲格列酮是一种口服活性降糖药，已证实在糖尿病动物模型和非胰岛素依赖型糖尿病（NIDDM）患者中，它可改善胰岛素抵抗和高胰岛素血症。为了确定该药物是否能预防高血糖诱导的胰岛素抵抗的发生，并研究其可能的发生机制，我们研究了曲格列酮对高血糖大鼠或输注氨基葡萄糖大鼠胰岛素作用的影响。正常雄性SD大鼠喂食含或不含曲格列酮（0.2%，作为食物添加剂）的常规粉状饲料。2周后，通过输注葡萄糖（52 mg·kg⁻¹·min⁻¹）和生长抑素（0.8 μg·kg⁻¹·min⁻¹）使大鼠血糖升高，或输注氨基葡萄糖（6.5 mg·kg⁻¹·min⁻¹）6.5小时。采用高胰岛素-正常血糖钳夹技术，以次最大（24 pmol·kg⁻¹·min⁻¹）或最大（240 pmol·kg⁻¹·min⁻¹）胰岛素输注速率测定体内胰岛素作用。与输注生理盐水的动物相比（8.0±0.2 mmol/L；P<0.001），输注葡萄糖和生长抑素导致血浆葡萄糖浓度显著升高（19.8±0.6 mmol/L）。高血糖导致胰岛素抵抗，与对照组相比，次最大葡萄糖处置率（GDR）显著降低（78±7 vs. 135±6 μmol·kg⁻¹·min⁻¹；P<0.01）以及最大GDR显著降低（141±9 vs. 237±6 μmol·kg⁻¹·min⁻¹；P<0.01）即可证明。曲格列酮治疗在很大程度上预防了高血糖诱导的次最大GDR（116±7 μmol·kg⁻¹·min⁻¹）和最大GDR降低（209±9 μmol·kg⁻¹·min⁻¹；P<0.05）。输注氨基葡萄糖也导致次最大GDR显著降低（85±3 vs. 135±6 μmol·kg⁻¹·min⁻¹；P<0.01）以及最大GDR显著降低（137±14 vs. 237±6 μmol·kg⁻¹·min⁻¹；P<0.01），与对照组相比。与高血糖动物的结果相反，曲格列酮治疗对氨基葡萄糖诱导的胰岛素抵抗没有影响。总之，1）在正常大鼠中，实验性高血糖以及输注氨基葡萄糖均导致外周和肝脏明显的胰岛素抵抗状态；2）曲格列酮治疗预防了高血糖诱导的而非氨基葡萄糖诱导的胰岛素抵抗；3）要么曲格列酮作用于氨基葡萄糖进入己糖胺途径之前的一个或多个位点，要么通过己糖胺途径的葡萄糖衍生产物通量增加不是这些动物中高血糖诱导的胰岛素作用缺陷的主要机制。
