Hsieh P-S, Tsai H-C, Kuo C-H, Chan J Y-H, Shyu J-F, Cheng W-T, Liu T-T
Department of Physiology & Biophysics, National Defence Medical Centre, Taipei, Taiwan.
Eur J Clin Invest. 2008 Nov;38(11):812-9. doi: 10.1111/j.1365-2362.2008.02026.x.
The effects of cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2) inhibition on insulin resistance in subjects with the metabolic syndrome remain elusive. Aims of this study were to examine the effects of COX1 and COX2 inhibitors on whole body and muscular insulin resistance in fructose-fed rats, an animal model of the metabolic syndrome.
The rats on regular or 60% fructose-enriched diets for 6 weeks were further divided into rats combined with or without piroxicam (a selective COX1 inhibitor) or celecoxib (a selective COX2 inhibitor) treatment for an additional 2 weeks. Euglycaemic hyperinsulinaemic clamp (EHC) with a tracer dilution method was performed at the end of the study.
The present result showed that fructose-induced increases in systolic blood pressure and fasting plasma insulin levels were significantly suppressed in rats treated with celecoxib but not piroxicam. In the EHC period, celecoxib significantly reversed fructose-induced decreases in whole body glucose uptake, mainly by glucose storage. Hepatic glucose production and whole body glycolysis were not significantly changed among groups. Celecoxib but not piroxicam significantly reversed fructose-induced decreases in glycogen synthase activities in red and white quadriceps muscles and insulin-stimulated membrane GLUT4 recruitment in soleus muscles. Celecoxib and piroxicam both significantly diminished fructose-induced increases in plasma thromboxane B2 and 6-keto prostaglandin (PG) F1alpha; but only celecoxib treatment significantly attenuated a fructose-induced increase in 8-isoprostane levels. Plasma PGE metabolites were not different among groups.
This study demonstrates that a therapeutic dose of celecoxib, but not piroxicam, could significantly attenuate fructose-induced whole body and muscular insulin resistance in rats.
环氧化酶 -1（COX1）和环氧化酶 -2（COX2）抑制对代谢综合征患者胰岛素抵抗的影响仍不明确。本研究的目的是在果糖喂养的大鼠（一种代谢综合征动物模型）中检测COX1和COX2抑制剂对全身及肌肉胰岛素抵抗的影响。
将喂食常规或60%果糖丰富饮食6周的大鼠进一步分为联合或不联合吡罗昔康（一种选择性COX1抑制剂）或塞来昔布（一种选择性COX2抑制剂）治疗2周的大鼠组。在研究结束时采用示踪剂稀释法进行正常血糖高胰岛素钳夹试验（EHC）。
目前结果显示，塞来昔布治疗的大鼠果糖诱导的收缩压和空腹血浆胰岛素水平升高得到显著抑制，而吡罗昔康治疗组未出现此现象。在EHC期间，塞来昔布主要通过葡萄糖储存显著逆转了果糖诱导的全身葡萄糖摄取减少。各组间肝葡萄糖生成和全身糖酵解无显著变化。塞来昔布而非吡罗昔康显著逆转了果糖诱导的红、白股四头肌糖原合酶活性降低以及比目鱼肌中胰岛素刺激的膜葡萄糖转运蛋白4（GLUT4）募集减少。塞来昔布和吡罗昔康均显著降低了果糖诱导的血浆血栓素B2和6 -酮前列腺素（PG）F1α升高；但只有塞来昔布治疗显著减弱了果糖诱导的8 -异前列腺素水平升高。各组间血浆前列腺素E代谢产物无差异。
本研究表明，治疗剂量的塞来昔布而非吡罗昔康可显著减轻果糖诱导的大鼠全身及肌肉胰岛素抵抗。
