摘要
胰岛素抵抗在危重病人中十分常见,严重影响危重病人的预后。丙泊酚可引起大鼠胰岛素抵抗,但具体机制尚不清楚。为了从分子水平探讨丙泊酚影响肝脏胰岛素抵抗的机制,本研究以正常培养的小鼠原代肝细胞及TNF-α诱导产生胰岛素抵抗的小鼠原代肝细胞为研究对象,检测丙泊酚对胰岛素信号通路关键酶磷酸化水平和细胞内糖原水平的影响,结果显示,丙泊酚可显著降低正常培养小鼠原代肝细胞Akt(Ser473)和GSK-3p(Ser9)的磷酸化水平,抑制PI3K/Akt/GSK-3β信号通路,抑制肝细胞糖原合成,从而引起小鼠原代肝细胞胰岛素抵抗。对于TNF-α诱导产生胰岛素抵抗的小鼠原代肝细胞,丙泊酚预处理可缓解TNF-α对小鼠原代肝细胞PI3K/Akt/GSK-3β信号通路及糖原合成的抑制,提示丙泊酚对TNF-α导致的小鼠原代肝细胞胰岛素抵抗有保护作用。
在大多数手术、创伤和危重病(如烧伤、脓毒血症)中胰岛素抵抗是常见的一种代谢紊乱,并伴有高血糖。在危重病人(特别是手术病人)中,高血糖伴随着死亡率上升、易感性增加、多发性神经病变、肾功能不全、输血需求增加、机械通气时间延长、入住ICU需求增加和住院时间延长。有研究表明,通过胰岛素强化治疗来严格控制血糖可降低创伤感染的风险并降低ICU病人的发病率和死亡率；虽然也有与之有争议的结果报道,但至少可以推测这些有争议的结果部分是由于胰岛素强化治疗所引发严重低血糖的机率增高所致。
有研究发现,丙泊酚麻醉可引起大鼠显著的全身性胰岛素抵抗,在丙泊酚麻醉大鼠的骨骼肌和心肌组织中由胰岛素引起的葡萄糖摄取减少,肝糖输出增加,结果表明在肌肉中由胰岛素引起的葡萄糖摄取减弱及肝糖输出抑制受损与丙泊酚引起的全身性胰岛素抵抗有关。
丙泊酚是目前最常用的静脉麻醉药,不仅用于各种手术的麻醉诱导和麻醉维持,而且还用于ICU病人的长时间镇静。丙泊酚在临床上广泛用于已知或未知患有胰岛素抵抗的病人,但是排除手术应激及脂溶性载体等因素,单独应用丙泊酚对胰岛素信号通路及胰岛素抵抗的影响尚无深入研究。丙泊酚是否会加重危重病人的胰岛素抵抗?发生胰岛素抵抗的危重病人输注丙泊酚是否安全?在本研究中,我们选取胰岛素作用的经典靶器官肝脏,同时也是调控糖脂代谢最重要的脏器,观察丙泊酚对小鼠原代肝细胞胰岛素抵抗的影响,探讨丙泊酚影响肝脏胰岛素抵抗的分子机制,为针对性地预防和治疗危重病人胰岛素抵抗提供更充分的科学依据,同时指导我们在临床麻醉工作中选择合适的麻醉方式和麻醉用药。
第一章丙泊酚可引起小鼠原代肝细胞胰岛素抵抗
目的探讨丙泊酚对小鼠原代肝细胞胰岛素抵抗的影响。
方法采用MTT法检测不同浓度丙泊酚培养条件下,小鼠原代肝细胞活力的变化。用终浓度为10μg/ml的丙泊酚处理小鼠原代肝细胞24h, Western blot检测PI3K/Akt/GSK-3β信号通路,蒽酮法检测糖原合成。用终浓度为10μg/ml的丙泊酚处理小鼠原代肝细胞24h, Western blot检测PTEN蛋白含量,RT-PCR检测PTEN mRNA表达。所有数据代表3次独立重复实验所得样本的均值。采用SPSS19.0统计学软件(SPSS Inc., Chicago, USA),计量资料以均数±标准差(斑s)表示,两组间比较采用t检验,多组间比较采用单因素方差分析,多重比较采用Tukey检验。方差不齐时采用Welch校正,多重比较采用Tamhane's T2检验。P<0.05为差异有统计学意义。
结果在一定浓度范围内(1～25μg/ml丙泊酚对小鼠原代肝细胞活性无显著影响,但随着丙泊酚浓度增高,小鼠原代肝细胞活性逐渐下降。当丙泊酚终浓度达到100μg/ml时,小鼠原代肝细胞活性下降至对照组的35±5%(P=0.000)。在明确不同浓度丙泊酚对小鼠原代肝细胞活力的影响后,根据实验结果并结合临床及相关文献,选取10μg/ml丙泊酚终浓度,检测不同培养时间下丙泊酚对小鼠原代肝细胞活力的影响,结果显示培养32h后,小鼠原代肝细胞活力无显著变化(P=0.949,F=0.216)。丙泊酚处理后pAkt(Ser473)和pGSK-3β(Ser9)相对降低,糖原合成减少；用丙泊酚(终浓度10μg/m1)和LiCl (终浓度20μ mol/L)处理小鼠原代肝细胞24h,Propofol+LiCl组与DMSO组相比较,两者在糖原合成上无显著差异(P=0.649),在pGSK-3β(Ser9)/GSK-3p上无显著差异(P=0.079),但在pAkt(Ser473)/Akt上两者差异有统计学意义(P=0.024)。丙泊酚处理后PTEN蛋白表达升高(P=0.001), PTEN mRNA水平升高(P=0.026)。
结论丙泊酚抑制小鼠原代肝细胞PI3K/Akt/GSK-3β信号通路。丙泊酚可引起小鼠原代肝细胞胰岛素抵抗。GSK-3β (Ser9)磷酸化受到抑制是丙泊酚抑制小鼠原代肝细胞糖原合成的关键环节。丙泊酚引起小鼠原代肝细胞胰岛素抵抗的作用靶点在GSK-3β上游。丙泊酚从上游抑制了小鼠原代肝细胞PI3K/Akt/GSK-3β信号通路。
第二章PTEN基因沉默可逆转丙泊酚引起的小鼠原代肝细胞胰岛素抵抗
目的探讨PTEN在丙泊酚所致小鼠原代肝细胞胰岛素抵抗中所起的作用及所处的位置,为治疗丙泊酚的不良反应寻找可能的干预靶点。
方法Cy3标记的siRNA转染小鼠原代肝细胞,用荧光显微镜观察其亚细胞分布定位。在小鼠原代肝细胞中转染公司合成的三段siRNA24h,设计并筛选得到有效干扰PTEN表达的siRNA片段。在小鼠原代肝细胞中同时加入丙泊酚(终浓度10gg/m1)和siR-996,培养24h, Western blot检测PI3K/Akt/GSK-3p信号通路,蒽酮法检测糖原合成。所有数据代表3次独立重复实验所得样本的均值。采用SPSS19.0统计学软件(SPSS Inc., Chicago, USA),计量资料以均数±标准差(x±s)表示,两组间比较采用t检验,多组间比较采用单因素方差分析,多重比较采用Tukey检验。方差不齐时采用Welch校正,多重比较采用Tamhane's T2检验。P<0.05为差异有统计学意义。
结果Cy3标记的siRNA转染10min后,在小鼠原代肝细胞中Cy3-siRNA的转染效率大于95%。与negative control组比,siR-996能够最有效抑制PTEN表达,PTEN蛋白表达降低至对照组的51±5%(P=0.000), PTEN mRNA水平降低至对照组的45+5%(P=0.000)。当PTEN基因沉默后,siR-996+Propofol组与NC+DMSO组相比较,两者在糖原合成上无显著差异(P=0.967),在pGSK-3β(Ser9)/GSK-3β上无显著差异(P=0.846),在pAkt(Ser473)/Akt上无显著差异(P0.757)。
结论丙泊酚引起小鼠原代肝细胞胰岛素抵抗的作用靶点可能在PTEN或其上游。
第三章丙泊酚对TNF-α导致的小鼠原代肝细胞胰岛素抵抗有保护作用
目的观察丙泊酚对TNF-α导致的小鼠原代肝细胞胰岛素抵抗的影响,探讨丙泊酚影响肝脏胰岛素抵抗的机制。
方法用终浓度为10ng/ml的TNF-α处理小鼠原代肝细胞24h, Western blot检测PI3K/AKT/GSK-3β信号通路,蒽酮法检测糖原合成。用终浓度为10gg/ml的丙泊酚处理小鼠原代肝细胞6h,然后加入终浓度为10ng/ml的TNF-a处理小鼠原代肝细胞24h,Western blot检测PI3K/Akt/GSK-3p信号通路,蒽酮法检测糖原合成。所有数据代表3次独立重复实验所得样本的均值。采用SPSS19.0统计学软件(SPSS Inc., Chicago, USA),计量资料以均数±标准差(x±s)表示,两组间比较采用t检验,多组间比较采用单因素方差分析,多重比较采用Tukey检验。方差不齐时采用Welch校正,多重比较采用Tamhane's T2检验。P<0.05为差异有统计学意义。
结果TNF-α处理24h后pAkt(Ser473)/Akt降低至对照组的45+12%(P=0.001),pGSK-3p(Ser9)/GSK-3(3降低至对照组的47±11%(P=0.001),糖原合成减少至对照组的49+10%(P=0.001)。用终浓度为10μg/ml的丙泊酚处理小鼠原代肝细胞6h,然后加入终浓度为10ng/ml的TNF-α处理小鼠原代肝细胞24h,Propofol+TNF-α组在PAkt(Ser473)/Akt、pGSK-3β(Ser9)/GSK-3β及糖原合成上均高于DMSO+TNF-α组(P=0.000;P=0.002；P=0.031)。
结论用TNF-α处理小鼠原代肝细胞,可成功构建胰岛素抵抗的细胞模型。丙泊酚对TNF-α导致的小鼠原代肝细胞胰岛素抵抗有保护作用,但这种保护作用并不是通过直接作用于PI3K-Akt信号通路实现的。
全文结论
1、丙泊酚抑制小鼠原代肝细胞PI3K/Akt/GSK-3β信号通路,引起小鼠原代肝细胞胰岛素抵抗。
2、GSK-3β(Ser9)磷酸化受到抑制是丙泊酚抑制小鼠原代肝细胞糖原合成的关键环节,丙泊酚引起小鼠原代肝细胞胰岛素抵抗的作用靶点在GSK-3β上游。
3、丙泊酚引起小鼠原代肝细胞胰岛素抵抗的作用靶点可能在PTEN或其上游。
4、丙泊酚对TNF-α导致的小鼠原代肝细胞胰岛素抵抗有保护作用,但这种保护作用并不是通过直接作用于PI3K-Akt信号通路实现的。
Insulin resistance is very common in critical patients and seriously influences their prognosis. Propofol may cause the insulin resistance of rats, but the specific mechanism is still unknown. In order to determine the mechanism of propofol influencing the insulin resistance of liver on the molecular level, the primary mouse hepatocytes cultured normally and the TNF-a induced primary mouse hepatocytes with insulin resistance were used as research materials. The effects of propofol on the phosphorylation level of key enzymes of insulin signaling pathway and the glycogen content in the cells were detected. The results indicated that propofol could considerably reduce the phosphorylation levels of Akt (Ser473) and GSK-3β (Ser9) in the primary mouse hepatocytes cultured normally, inhibit the signal pathway PI3K/Akt/GSK-3β and the glycogen synthesis of hepatocytes. Thus, the insulin resistance of primary mouse hepatocytes was induced. For the TNF-a-induced primary mouse hepatocytes with insulin resistance, the pretreatment with propofol could alleviate the inhibitory effect of TNF-a on the signal pathway PI3K/Akt/GSK-3β and the glycogen synthesis of primary mouse hepatocytes. This means that propofol had protective effect against the insulin resistance of primary mouse hepatocytes induced by TNF-a.
Insulin resistance is a common denominator in metabolic derangements associated with major surgery, trauma and critical illness (e.g., burn, sepsis) and is associated with hyperglycemia. Hyperglycemia in critically ill patients is associated with increased mortality and susceptibility to infection, polyneuropathy, renal insufficiency, and need for transfusion, increased ventilator-dependent days, intensive care unit (ICU) stay, and hospital stay, particularly in surgical patients. Tight control of blood glucose levels by intensive insulin therapy has been shown to decrease the risk of wound infection, and reduce the morbidity and mortality in intensive care units, although controversial results were also reported, presumably at least in part due to increased incidence of severe hypoglycemia by intensive insulin therapy.
A prospective study found that anesthesia with propofol resulted in whole-body insulin resistance, attenuated insulin-stimulated glucose uptake in skeletal muscle and heart, and attenuated insulin-mediated inhibition of hepatic glucose output. The results indicate that attenuated insulin-stimulated glucose uptake in muscle and impaired insulin-mediated inhibition of hepatic glucose output are involved in propofol-induced systemic insulin resistance. Propofol (2,6,-diisopropylphenol) has been clinically used not only for induction and maintenance of anesthesia during surgical procedures but also for long-term sedation of patients in the ICUs. However, there is still no research about the effect of single use of propofol on the insulin signaling pathway and insulin resistance with exclusion of the effects of other factors such as surgical stress and fat-soluble carrier. Then the following questions arise:will propofol aggravate the insulin resistance in critical patients? Is it safe to inject propofol for the critical patients with insulin resistance? In this article, the liver, as the major target organ of insulin and the most important organ regulating the glucolipid metabolism, was used. The effects of propofol on insulin resistance in primary mouse hepatocytes were observed to discuss the molecular mechanism of propofol influencing the insulin resistance of liver. The research results provide the scientific bases for the targeted prevention and treatment of insulin resistance in critical patients, and guide us in choosing appropriate anesthetic methods and drugs clinically.
Chapter1Propofol induces insulin resistance in mouse primary hepatocytes
Objective To explore the effects of propofol on insulin resistance in mouse primary hepatocytes.
Methods MTT assay was used to detect changes in mouse primary hepatocytes viability in propofol culture conditions with different concentrations. With a final concentration of10μg/ml propofol treated mouse primary hepatocytes for24h, Western blot was used to detect PI3K/Akt/GSK-3p signaling pathway, anthrone was used to assay glycogen synthesis. With a final concentration of10μg/ml propofol treated mouse primary hepatocytes for24h, Western blot was used to detect PTEN protein levels, RT-PCR was used to detect the expression of PTEN mRNA. All data represent the mean of duplicate samples from3separately performed experiments. Results were expressed as mean and standard deviation (mean±SD). Data analysis was performed with SPSS19.0statistical software (SPSS Inc., Chicago, USA). Difference was analyzed for significance by Student's t test between two groups and one-way ANOVA followed by Tukey's test (homogeneity of variance) or Tamhane's T2test (inhomogeneity of variance) among many groups. A value of P<0.05was considered statistically significant.
Results Within a certain range of concentrations, propofol has no effects on viability, but with the propofol concentration greater than25μg/ml final concentration of culture, the cell viability decreased, when the final concentration of propofol come to100μg/ml, cell viability decreased to about30%(P<0.001). When we knew the effects of propofol on mouse primary hepatocytes viability, we chose10μg/ml propofol to detect the effects of propofol on mouse primary hepatocytes viability in different culture time,32hours later, there was no significant changes in mouse primary hepatocytes viability(P>0.05). After treatment with Propofol the pAkt(Ser473) and pGSK-3β(Ser9) is relatively lower and glycogen synthesis reduced in mouse primary hepatocytes.20μmol/L LiCl could eliminate the inhibitory effect of propofol on glycogen synthesis in mouse primary hepatocytes, but could not completely eliminate the inhibition of propofol on PI3K/Akt/GSK-3β signaling pathway. After treatment with propofol PTEN protein expression increased, PTEN mRNA levels increased relatively in mouse primary hepatocytes.
Conclusion10μg/ml propofol inhibited glycogen synthesis in mouse primary hepatocytes, propofol induces insulin resistance in mouse primary hepatocytes.10μg/ml propofol could significantly reduce the pAkt(Ser473)/Akt level, and lower levels of pGSK-3β(Ser9)/GSK-3β, propofol inhibited PI3K/Akt/GSK-3β signaling pathway in mouse primary hepatocytes, thus propofol causes insulin resistance in mouse primary hepatocytes. LiCl could eliminate the inhibitory effect of propofol on glycogen synthesis in mouse primary hepatocytes, this shows that from the negative the inhibition of GSK-3β(Ser9) phosphorylation is the key that propofol inhibited glycogen synthesis in mouse primary hepatocytes. LiCl could not completely eliminate the inhibition of propofol on PI3K/Akt/GSK-3β signaling pathway, it draws a conclusion that the target on which propofol induced insulin resistance in mouse primary hepatocytes is at the upstream of GSK-3β.10μg/ml propofol enhanced PTEN expression at the levels of transcription and protein expression in mouse primary hepatocytes, thereby propofol affected the phosphorylation of Akt and GSK-3β at the downstream, propofol suppressed the PI3K/Akt/GSK-3β signaling pathway from upstream in mouse primary hepatocytes.
Chapter2PTEN gene silencing reverses propofol-induced insulin resistance in mouse primary hepatocytes
Objective To investigate the role of PTEN at propofol-induced insulin resistance in mouse primary hepatocytes, and looking for possible intervention target for the treatment of adverse effects of propofol.
Methods Cy3-labeled siRNA transfected into mouse primary hepatocytes, its subcellular distribution was observed by fluorescence microscopy. There kinds of sythesis siRNAs transfected into mouse primary hepatocytes for24h, the siRNA would be selected which could interfere with PTEN expression the most effectively. Propofol and siR-996were mixed with mouse primary hepatocytes, incubated for24hours, Western blot was used to detect PI3K/Akt/GSK-3β signaling pathway, anthrone was used to assay glycogen synthesis. All data represent the mean of duplicate samples from3separately performed experiments. Results were expressed as mean and standard deviation (mean±SD). Data analysis was performed with SPSS19.0statistical software (SPSS Inc., Chicago, USA). Difference was analyzed for significance by Student's t test between two groups and one-way ANOVA followed by Tukey's test (homogeneity of variance) or Tamhane's T2test (inhomogeneity of variance) among many groups. A value of P<0.05was considered statistically significant.
Results When Cy3-labeled siRNA transfected into mouse primary hepatocytes for10min, Cy3-siRNA transfection efficiency was greater than95%. Compared with the negative control group, siR-996could inhibit the expression of PTEN the most effectively, PTEN protein expression decreased50%, PTEN mRNA levels were also reduced accordingly. PTEN gene silencing reversed the inhibition of propofol on PI3K/AKT/GSK-3β signaling pathway and glycogen synthesis in mouse primary hepatocytes.
Conclusion PTEN gene silencing reversed the inhibition of propofol on PI3K/AKT/GSK-3β signaling pathway and glycogen synthesis in mouse primary hepatocytes, eliminated insulin resistance induced by propofol in mouse primary hepatocytes, it draws a conclusion that PTEN or someone at whose upstream is the target on which propofol induced insulin resistance in mouse primary hepatocytes.
Chapter3Propofol could protect mouse primary hepatocytes against TNF-a-induced insulin resistance
Objective To observe the effects of propofol on TNF-α-induced insulin resistance in mouse primary hepatocytes, to investigate the mechanism of propofol affecting hepatic insulin resistance.
Methods With a final concentration of10ng/ml TNF-α treated mouse primary hepatocytes for24h, Western blot was used to detect PI3K/Akt/GSK-3β signaling pathway, anthrone was used to assay glycogen synthesis. With a final concentration of10μg/ml propofol treated mouse primary hepatocytes for6h, then mixed with10ng/ml TNF-α for24h, Western blot was used to detect PI3K/Akt/GSK-3β signaling pathway, anthrone was used to assay glycogen synthesis. All data represent the mean of duplicate samples from3separately performed experiments. Results were expressed as mean and standard deviation (mean±SD). Data analysis was performed with SPSS19.0statistical software (SPSS Inc., Chicago, USA). Difference was analyzed for significance by Student's t test between two groups and one-way ANOVA followed by Tukey's test (homogeneity of variance) or Tamhane's T2test (inhomogeneity of variance) among many groups. A value of P<0.05was considered statistically significant.
Results After TNF-α treatment pAkt(Ser473) and pGSK-3β(Ser9) was significantly reduced to45%and48%, glycogen synthesis reduced to49%. Compared with the TNF-a group, pAkt(Ser473) and pGSK-3β(Ser9) raised, glycogen synthesis increased.
Conclusion TNF-a could significantly reduce the pAkt(Ser473)/Akt level and pGSK-3p(Ser9)/GSK-3β level, TNF-a inhibited PI3K/Akt/GSK-3β signaling pathway and glycogen synthesis in mouse primary hepatocytes, thus TNF-α-induced insulin resistance model in mouse primary hepatocytes had been successfully constructed. Pretreatment with propofol alleviated the inhibition of TNF-α on PI3K/AKT/GSK-3β signaling pathway and glycogen synthesis in mouse primary hepatocytes, propofol has a protective effect against TNF-α-induced hepatic insulin resistance. Propofol has a protective effect against TNF-α-induced insulin resistance in mouse primary hepatocytes, however, the protective effect does not seem to realize through PI3K/Akt/GSK-3β signaling pathway, the specific protection mechanisms need to be further studied.
General conclusions
1.10μg/ml propofol inhibited glycogen synthesis in mouse primary hepatocytes, Propofol induces insulin resistance in mouse primary hepatocytes.
2.10μg/ml propofol could significantly reduce the pAkt(Ser473)/Akt level, and lower levels of pGSK-3β(Ser9)/GSK-3β, propofol inhibited PI3K/Akt/GSK-3β signaling pathway in mouse primary hepatocytes, thus propofol causes insulin resistance in mouse primary hepatocytes.
3. LiCl could eliminate the inhibitory effect of propofol on glycogen synthesis in mouse primary hepatocytes, this shows that from the negative the inhibition of GSK-3β(Ser9) phosphorylation is the key that propofol inhibited glycogen synthesis in mouse primary hepatocytes.
4. LiCl could not completely eliminate the inhibition of propofol on PI3K/Akt/GSK-3β signaling pathway, it draws a conclusion that the target on which propofol induced insulin resistance in mouse primary hepatocytes is at the upstream of GSK-3p.
5.10μg/ml propofol enhanced PTEN expression at the levels of transcription and protein expression in mouse primary hepatocytes, thereby propofol affected the phosphorylation of Akt and GSK-3β at the downstream, propofol suppressed the PI3K/Akt/GSK-3β signaling pathway from upstream in mouse primary hepatocytes.
6. PTEN gene silencing reversed the inhibition of propofol on PI3K/AKT/GSK-3p signaling pathway and glycogen synthesis in mouse primary hepatocytes, eliminated insulin resistance induced by propofol in mouse primary hepatocytes, it draws a conclusion that PTEN or someone at whose upstream is the target on which propofol induced insulin resistance in mouse primary hepatocytes.
7. TNF-a could significantly reduce the pAkt(Ser473)/Akt level and pGSK-3β(Ser9)/GSK-3β level, TNF-a inhibited PI3K/Akt/GSK-3p signaling pathway and glycogen synthesis in mouse primary hepatocytes, thus TNF-a-induced insulin resistance model in mouse primary hepatocytes had been successfully constructed.
8. Pretreatment with propofol alleviated the inhibition of TNF-a on PI3K/AKT/GSK-3β signaling pathway and glycogen synthesis in mouse primary hepatocytes, propofol has a protective effect against TNF-a-induced hepatic insulin resistance.
9. Propofol has a protective effect against TNF-a-induced insulin resistance in mouse primary hepatocytes, however, the protective effect does not seem to realize through PI3K/Akt/GSK-3β signaling pathway, the specific protection mechanisms need to be further studied.
引文
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[1]Lipshutz AK, Gropper MA. Perioperative glycemic control:an evidence-based review[J]. Anesthesiology,2009,110(2):408-21.
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[5]van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients[J]. N Engl J Med Overseas Ed,2001,345(19):1359-67.
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[10]Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis[J]. N Engl J Med Overseas Ed,2008,358(2):125-39.
[11]Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery:a randomized trial[J]. Ann Intern Med, 2007,146(4):233-43.
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[13]Ford ES, Giles WH. A comparison of the prevalence of the metabolic syndrome using two proposed definitions [J]. Diabetes Care,2003,26(3):575-81.
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[15]贾伟平.中国人代谢综合征的现状及临床特征[J].中华内分泌代谢杂志,2006,22(3)：增录3S-6-增录3S-8.
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