Naples Mark, Federico Lisa M, Xu Elaine, Nelken Joanna, Adeli Khosrow
Clinical Biochemistry and Molecular Structure & Function, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Atherosclerosis. 2008 May;198(1):94-103. doi: 10.1016/j.atherosclerosis.2007.11.003. Epub 2008 Feb 21.
Statin-treatment of fructose-fed/insulin resistant hamsters was recently shown to ameliorate metabolic dyslipidemia and hepatic VLDL overproduction. Here, we provide evidence that rosuvastatin treatment of insulin resistant hamsters can induce improvements in hepatic and whole body insulin sensitivity. Treatment with 10 mg/kg/day rosuvastatin for 10 days significantly reduced fasting insulin (-59%) and triglyceride (-50%) levels in fructose-fed hamsters (p<0.05). Following an intraperitoneal (IP) glucose challenge, rosuvastatin-treated hamsters exhibited enhanced glucose clearance compared to untreated hamsters maintained on the high-fructose diet (area under curve (AUC)=1772+/-223 mM min vs. 2413+/-253 mM min, respectively; p<0.002) with a significant reduction in 2h post-challenge glucose (n=5, p<0.02). Rosuvastatin-treatment also significantly improved sensitivity to an IP insulin challenge (AUC=314+/-39 mM min vs. 195+/-22 mM min for rosuvastatin-treated and fructose-fed hamsters, respectively; p<0.04, n=3). At the molecular level, significant increases in tyrosine-phosphorylation of the hepatic insulin receptor and IRS-1 were observed for rosuvastatin-treated hamsters (+37% and +58%, respectively) compared to fructose-fed controls following an intravenous (IV) bolus of insulin (p<0.05). Increases in insulin receptor and IRS-1 phosphorylation were also observed in muscle and adipose tissue. Analysis of hepatic Akt phosphorylation and mass revealed a small (25%) increase in serine phosphorylation of Akt with no significant change in Akt mass, although serine-phosphorylation and mass of Akt2 were significantly increased (+32%, p=0.03, and +42%, p=0.01, respectively). Interestingly, expression of PTP-1B, a key negative regulator of insulin signaling, showed a non-significant trend toward reduction in liver and was significantly reduced in adipose tissue (-20% and -37%, respectively). Taken together, these data suggest that statin-treatment increases whole body and peripheral tissue insulin sensitivity via improved cellular insulin signal transduction.
近期研究表明，对喂食果糖/胰岛素抵抗的仓鼠进行他汀类药物治疗可改善代谢性血脂异常及肝脏极低密度脂蛋白（VLDL）过量生成。在此，我们提供证据表明，瑞舒伐他汀治疗胰岛素抵抗的仓鼠可改善肝脏及全身的胰岛素敏感性。以10mg/kg/天的剂量对果糖喂养的仓鼠进行10天的瑞舒伐他汀治疗，显著降低了空腹胰岛素水平（-59%）和甘油三酯水平（-50%）（p<0.05）。腹腔注射葡萄糖后，与维持高果糖饮食的未治疗仓鼠相比，瑞舒伐他汀治疗的仓鼠葡萄糖清除能力增强（曲线下面积（AUC）分别为1772±223mM·min和2413±253mM·min；p<0.002），且注射后2小时血糖显著降低（n=5，p<0.02）。瑞舒伐他汀治疗还显著改善了对腹腔注射胰岛素的敏感性（瑞舒伐他汀治疗的果糖喂养仓鼠和未治疗的果糖喂养仓鼠的AUC分别为314±39mM·min和195±22mM·min；p<0.04，n=3）。在分子水平上，静脉注射胰岛素后，与果糖喂养的对照仓鼠相比，瑞舒伐他汀治疗的仓鼠肝脏胰岛素受体和胰岛素受体底物-1（IRS-1）的酪氨酸磷酸化显著增加（分别增加37%和58%）（p<0.05）。在肌肉和脂肪组织中也观察到胰岛素受体和IRS-1磷酸化增加。对肝脏Akt磷酸化和含量的分析显示，Akt的丝氨酸磷酸化有小幅（25%）增加，而Akt含量无显著变化，尽管Akt2的丝氨酸磷酸化和含量显著增加（分别增加32%，p=0.03，和42%，p=0.01）。有趣的是，胰岛素信号关键负调节因子蛋白酪氨酸磷酸酶-1B（PTP-1B）的表达在肝脏中呈非显著下降趋势，在脂肪组织中显著降低（分别降低20%和37%）。综上所述，这些数据表明他汀类药物治疗可通过改善细胞胰岛素信号转导来提高全身及外周组织的胰岛素敏感性。
