PTP1B基因缺失在脓毒症胰岛素抵抗大鼠中的作用及可能机制

Role and possible mechanism of PTP1B gene deletion in septic rats with insulin resistance

目的探讨敲除蛋白酪氨酸磷酸酶1B(PTP1B)基因对脓毒症所致胰岛素抵抗大鼠的干预作用及可能机制。方法将20只敲除PTP1B基因的大鼠分为PTP1B(-/-)假手术组和PTP1B(-/-)脓毒症组各10只,将20只野生型大鼠分为野生型假手术组和野生型脓毒症组各10只。PTP1B(-/-)脓毒症组和野生型脓毒症组均建立脓毒症胰岛素抵抗大鼠模型,其他两组仅进行假手术。于术后12 h检测各组大鼠的稳态模型评估胰岛素抵抗(HOMA-IR)指数,于手术后24 h测定各组大鼠血清肿瘤坏死因子α(TNF-α)水平、肝脏组织蛋白激酶B(Akt)磷酸化水平[磷酸化Akt(p-Akt)/Akt]以及葡萄糖转运蛋白2(GLUT-2)向肝细胞膜转移情况。结果野生型脓毒症组、PTP1B(-/-)脓毒症组的HOMA-IR指数、血清TNF-α水平分别高于野生型假手术组、PTP1B(-/-)假手术组,而p-Akt/Akt和GLUT-2在肝细胞膜中的表达分别低于野生型假手术组、PTP1B(-/-)假手术组(均P<0.05)。PTP1B(-/-)脓毒症组大鼠的HOMA-IR指数、血清TNF-α水平低于野生型脓毒症组,而Akt磷酸化水平以及GLUT-2在肝细胞膜中的表达均高于野生型脓毒症组(均P<0.05)。结论在大鼠中敲除PTP1B基因可以改善脓毒症所致胰岛素抵抗,其机制可能是减轻细胞外的炎症因子水平从而缓解对胰岛素受体的竞争效应,以及改变细胞内的胰岛素信号转导通路。

Objective To explore the intervention effect and possible mechanism of protein tyrosine phosphatase 1B(PTP1B)gene knockout on rats with sepsis-caused insulin resistance.Methods Twenty rats with PTP1B gene knockout were divided into PTP1B(-/-)sham operation group(n=10)and PTP1B(-/-)sepsis group(n=10);20 wild-type rats were divided into wild-type sham operation group(n=10)and wild-type sepsis group(n=10).Rat models of sepsis-caused insulin resistance were established in the PTP1B(-/-)sepsis and wild-type sepsis groups,and the other two groups undertook sham operations alone.Twelve hours after the operation,the homeostasis model assessment-insulin resistance(HOMA-IR)index of rats was determined in rats of each group,and 24 hours after the operation,serum tumor necrosis factorα(TNF-α)level,the phosphorylation level of protein kinase B(Akt)in liver tissues(phosphorylated Akt[p-Akt]/Akt),and glucose transporter 2(GLUT-2)transfer to liver cell membrane were detected in rats of each group.Results The HOMA-IR index and serum TNF-αlevel were higher and p-Akt/Akt and GLUT-2 expression in liver cell membrane were lower in the wild-type sepsis and PTP1B(-/-)sepsis groups than in the wild-type sham operation and PTP1B(-/-)sham operation groups(all P<0.05).Rats in the PTP1B(-/-)sepsis group exhibited lower HOMA-IR index and serum TNF-αlevel,a higher phosphorylation level of Akt,and an elevation in the expression of GLUT-2 in liver cell membrane as compared with the wild-type sepsis group(all P<0.05).Conclusion Knockout of PTP1B gene in rats can improve sepsis-caused insulin resistance,and its mechanism may be to reduce the levels of extracellular inflammatory factors so as to attenuate the competition effects for insulin receptors as well as to modify the intracellular insulin signal transduction pathway.