褪黑素对体内体外高脂诱导胰岛素抵抗的预防作用及机制研究
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摘要
2型糖尿病的发病主要是在遗传基础上综合多种环境因素的结果，其中高糖高脂饮食是一种重要的环境因素。2型糖尿病的主要临床特征是胰岛素抵抗及胰岛β细胞分泌功能异常，其中胰岛素抵抗是致病的主要因素，贯穿于其发生、发展的整个过程。已知肥胖所致的血浆游离肪酸浓度(FFA)增高是引起胰岛素抵抗和的重要危险因素之一。流行病学调查和实验室研究表明，饮食中脂肪摄入过多或脂肪过量储存(肥胖)均可导致胰岛素抵抗，血浆游离脂肪酸(FFA)浓度与肥胖、2型糖尿病等多种胰岛素抵抗状态相关，血浆升高的FFA是导致胰岛素抵抗的决定性因素，也是胰岛素抵抗脂毒学说的重要内容。
肝脏是机体调节葡萄糖代谢和脂代谢的重要器官，有研究发现FFA能促进肝脏葡萄糖输出，降低肝脏对胰岛素的敏感性，诱导肝脏胰岛素抵抗。肝脏是胰岛素作用的一个重要靶器官，肝脏中胰岛素信号转导途径的缺陷，会直接关系到全身胰岛素抵抗的发生和2型糖尿病的发病，因此对肝脏胰岛素抵抗发生机理和预防的研究已越来越受到人们的重视，随着研究不断的深入，将有利于我们进一步了解2型糖尿病的发病机理，并探寻早期预防方法。
营养过剩和体力活动减少导致细胞内葡萄糖和游离脂肪酸升高，线粒体的能量转换加快，自由基(ROS)的生成增加导致细胞氧化还原状态失衡，使细胞产生氧化应激。许多证据显示，氧化应激参与了胰岛素抵抗的形成，氧化应激也是糖尿病各种慢性并发症的共同基础，是2型糖尿病的重要致病因素。提高机体的抗氧化能力应该可以对抗高血糖和高游离脂肪酸的这种作用。
L02细胞源于人胚胎肝细胞，保留了原代肝细胞的许多基本表型和功能，包括细胞膜成分、代谢通路、生理浓度的各种酶以及活性基因表达，是很好的研究肝脏代谢和胰岛素信号传导的体外实验模型。
本课题体外实验以L02细胞为研究对象，用饱和脂肪酸软脂酸(palmitate，PA)和多不饱和脂肪酸亚油酸(Linoleic acid，LA)孵育L02细胞，诱导L02细胞胰岛素抵抗。为观察FFA对胞内胰岛素信号通路的影响，对胰岛素信号传递的主要蛋白如胰岛素受体(IR)、胰岛素受体底物IRS1／2、蛋白激酶B(PKB)、糖原合酶激酶3β(GSK-3β)、S6K、FOXO1等的活性变化进行检测；为观察FFA对细胞内抗氧化防御体系的影响，对细胞内活性氧ROS水平以及ROS活化的氧化应激敏感激酶c-Jun氨基末端激酶(c-jun N-terminal kinase)JNK活性进行测定；在PA孵育同时加入褪黑素(melatonin)，一种体内最强抗氧化作用的自由基清除剂，测定以上同样指标，观察褪黑素是否能影响胰岛素信号的传递而改善胰岛素抵抗；并分析褪黑素对LO2细胞形成胰岛素抵抗的预防作用及其机制。在体内动物实验以SD大鼠为研究对象，高脂饮食诱导形成大鼠胰岛素抵抗模型，同时每天腹腔注射给予褪黑素，通过检测血脂、血糖、血胰岛素、血和肝脏中氧化及抗氧化指标，以及鼠肝中以上多种信号蛋白、激酶的活性变化，观察分析高脂饮食诱导大鼠氧化应激和全身胰岛素抵抗的关系以及褪黑素的预防作用和机制，为临床上有效的预防和治疗胰岛素抵抗和2型糖尿病奠定理论基础和提供实验依据。
Type 2 diabetes is characterized by insulin resistance as well as pancreaticβ-celldysfunction, and is a multifactorial event, which is linked with genetic and enviromentalfactors, including hyperglycemia and high-fat diet. Insulin resistance is a cardial feature oftype 2 diabetes and often precedes the onset of type 2 diabetes by many years. Increasedplasma concentration of free fatty acids (FFA) is associated with many insulin resistancestates,including obesity and type 2 diabetes,and have been proposed to play a pathogenicrole in both peripheral and hepatic insulin resistance. FFA cause lipotoxicity to cells, whichfurther increase insulin resistance in muscle and liver and decrease insulin secretion bydamaging pancreatic beta-cells, leading to more severe diabetes.
The liver plays a major role in glucose homeostasis, based on its capacity for net glucoseuptake from the blood during hyperglycaemia, and net glucose release duringpostabsorptive and fasting periods. The lives is also an insulin sensitive organ that play akey role in the regulation of the whole body energy homeostasis.Insulin resistance inmetaboliccally very active hepatocytes is expected to have important systemicconsequences. Insulin resistance, particularly in the liver, is a critical feature of type 2diabetes mellitus. Although insulin resistance is a multifactorial disorder involving multiplemechanisms, a suspected cause of insulin resistance in the liver is the increased delivery offatty acids to this tissue and the hepatocellular deposition of excess lipid. A number ofstudies have indicated excessive supply of fatty acids to the liver might be a contributing factor to hepatic insulin resistance. The elevated plasma FFA can increase postabsorptivehepatic glucose production, reduce the ability of insulin to suppress hepatic glucose output,and attenuates insulin signal transduction.Thus, insight into the pathogenesis of hepaticinsulin resistance will pave the way to new therapeutic modalities for type 2 diabetes.Less physical activity and ovemutrition cause high glucose and elevated FFA in cells. Highglucose results in oxidative stress due to increased production of mitochondrial ROS andglucose autoxidation. Elevated FFA can cause oxidative stress due to increasedmitochondrial uncoupling andβ-oxidation, leading to the increased production of ROS.There is considerable evidence that hyperglycemia and FFA-induced oxidative stress playsa key role in causing late complications in type 1 and type 2 diabetes, along with insulinresistance. Studies with antioxidants suggest that new strategies may become available totreat these conditions
Human L02 liver cell line is an appropriate in vitro experimental model for study ofhepatic insulin signaling and glucose metabolism, which derived from healthy human liver,retaining the primary hepatocyte phenotype and function including plasma membranecomponents, metabolic pathways, physiological enzyme levels, and active gene expression.
In the present in vitro study, we investigated direct effects of saturated fatty acid palmiticacid (PA) and polyunsaturated fatty acid Linoleic acid (LA)on intracellular redox states andkey components of intracellular insulin signaling cascades as well as stress-sensitivepathway including insulin receptor (IR), insulin receptor substrate1/2(IRS1/2), PKB,GSK3β, FOXO, S6K and c-jun N-terminal kinase (JNK), in L02 cells with or withouttreatment of melatonin, a kind of potent antioxidant.
In the present in vivo study, after the rats were fed for 10 weeks, we investigated thealtered endogenous antioxidant defenses of the rats injected with melatoninintraperitoneally daily. We also measured fasting blood glucose (FPG) , fasting insulin(FINS) , triglyceride (TG), total cholesterin (TC), free fatty acids(FFA), high densitylipoprotein- cholesterin (HDL-C) in rat plasma. The focus was on key components of intracellular insulin signaling cascades as well as stress-sensitive pathway , including IR,IRS1/2, PKB, GSK3β, FOXO, and JNK in rat liver. Our study demonstrated melatonin canprotect L02 cells treated with FFA and rats fed with high fat diet against high-lipid-inducedinsulin resistance in vitro and in vivo.
肝脏是机体调节葡萄糖代谢和脂代谢的重要器官，有研究发现FFA能促进肝脏葡萄糖输出，降低肝脏对胰岛素的敏感性，诱导肝脏胰岛素抵抗。肝脏是胰岛素作用的一个重要靶器官，肝脏中胰岛素信号转导途径的缺陷，会直接关系到全身胰岛素抵抗的发生和2型糖尿病的发病，因此对肝脏胰岛素抵抗发生机理和预防的研究已越来越受到人们的重视，随着研究不断的深入，将有利于我们进一步了解2型糖尿病的发病机理，并探寻早期预防方法。
营养过剩和体力活动减少导致细胞内葡萄糖和游离脂肪酸升高，线粒体的能量转换加快，自由基(ROS)的生成增加导致细胞氧化还原状态失衡，使细胞产生氧化应激。许多证据显示，氧化应激参与了胰岛素抵抗的形成，氧化应激也是糖尿病各种慢性并发症的共同基础，是2型糖尿病的重要致病因素。提高机体的抗氧化能力应该可以对抗高血糖和高游离脂肪酸的这种作用。
L02细胞源于人胚胎肝细胞，保留了原代肝细胞的许多基本表型和功能，包括细胞膜成分、代谢通路、生理浓度的各种酶以及活性基因表达，是很好的研究肝脏代谢和胰岛素信号传导的体外实验模型。
本课题体外实验以L02细胞为研究对象，用饱和脂肪酸软脂酸(palmitate，PA)和多不饱和脂肪酸亚油酸(Linoleic acid，LA)孵育L02细胞，诱导L02细胞胰岛素抵抗。为观察FFA对胞内胰岛素信号通路的影响，对胰岛素信号传递的主要蛋白如胰岛素受体(IR)、胰岛素受体底物IRS1／2、蛋白激酶B(PKB)、糖原合酶激酶3β(GSK-3β)、S6K、FOXO1等的活性变化进行检测；为观察FFA对细胞内抗氧化防御体系的影响，对细胞内活性氧ROS水平以及ROS活化的氧化应激敏感激酶c-Jun氨基末端激酶(c-jun N-terminal kinase)JNK活性进行测定；在PA孵育同时加入褪黑素(melatonin)，一种体内最强抗氧化作用的自由基清除剂，测定以上同样指标，观察褪黑素是否能影响胰岛素信号的传递而改善胰岛素抵抗；并分析褪黑素对LO2细胞形成胰岛素抵抗的预防作用及其机制。在体内动物实验以SD大鼠为研究对象，高脂饮食诱导形成大鼠胰岛素抵抗模型，同时每天腹腔注射给予褪黑素，通过检测血脂、血糖、血胰岛素、血和肝脏中氧化及抗氧化指标，以及鼠肝中以上多种信号蛋白、激酶的活性变化，观察分析高脂饮食诱导大鼠氧化应激和全身胰岛素抵抗的关系以及褪黑素的预防作用和机制，为临床上有效的预防和治疗胰岛素抵抗和2型糖尿病奠定理论基础和提供实验依据。
Type 2 diabetes is characterized by insulin resistance as well as pancreaticβ-celldysfunction, and is a multifactorial event, which is linked with genetic and enviromentalfactors, including hyperglycemia and high-fat diet. Insulin resistance is a cardial feature oftype 2 diabetes and often precedes the onset of type 2 diabetes by many years. Increasedplasma concentration of free fatty acids (FFA) is associated with many insulin resistancestates,including obesity and type 2 diabetes,and have been proposed to play a pathogenicrole in both peripheral and hepatic insulin resistance. FFA cause lipotoxicity to cells, whichfurther increase insulin resistance in muscle and liver and decrease insulin secretion bydamaging pancreatic beta-cells, leading to more severe diabetes.
The liver plays a major role in glucose homeostasis, based on its capacity for net glucoseuptake from the blood during hyperglycaemia, and net glucose release duringpostabsorptive and fasting periods. The lives is also an insulin sensitive organ that play akey role in the regulation of the whole body energy homeostasis.Insulin resistance inmetaboliccally very active hepatocytes is expected to have important systemicconsequences. Insulin resistance, particularly in the liver, is a critical feature of type 2diabetes mellitus. Although insulin resistance is a multifactorial disorder involving multiplemechanisms, a suspected cause of insulin resistance in the liver is the increased delivery offatty acids to this tissue and the hepatocellular deposition of excess lipid. A number ofstudies have indicated excessive supply of fatty acids to the liver might be a contributing factor to hepatic insulin resistance. The elevated plasma FFA can increase postabsorptivehepatic glucose production, reduce the ability of insulin to suppress hepatic glucose output,and attenuates insulin signal transduction.Thus, insight into the pathogenesis of hepaticinsulin resistance will pave the way to new therapeutic modalities for type 2 diabetes.Less physical activity and ovemutrition cause high glucose and elevated FFA in cells. Highglucose results in oxidative stress due to increased production of mitochondrial ROS andglucose autoxidation. Elevated FFA can cause oxidative stress due to increasedmitochondrial uncoupling andβ-oxidation, leading to the increased production of ROS.There is considerable evidence that hyperglycemia and FFA-induced oxidative stress playsa key role in causing late complications in type 1 and type 2 diabetes, along with insulinresistance. Studies with antioxidants suggest that new strategies may become available totreat these conditions
Human L02 liver cell line is an appropriate in vitro experimental model for study ofhepatic insulin signaling and glucose metabolism, which derived from healthy human liver,retaining the primary hepatocyte phenotype and function including plasma membranecomponents, metabolic pathways, physiological enzyme levels, and active gene expression.
In the present in vitro study, we investigated direct effects of saturated fatty acid palmiticacid (PA) and polyunsaturated fatty acid Linoleic acid (LA)on intracellular redox states andkey components of intracellular insulin signaling cascades as well as stress-sensitivepathway including insulin receptor (IR), insulin receptor substrate1/2(IRS1/2), PKB,GSK3β, FOXO, S6K and c-jun N-terminal kinase (JNK), in L02 cells with or withouttreatment of melatonin, a kind of potent antioxidant.
In the present in vivo study, after the rats were fed for 10 weeks, we investigated thealtered endogenous antioxidant defenses of the rats injected with melatoninintraperitoneally daily. We also measured fasting blood glucose (FPG) , fasting insulin(FINS) , triglyceride (TG), total cholesterin (TC), free fatty acids(FFA), high densitylipoprotein- cholesterin (HDL-C) in rat plasma. The focus was on key components of intracellular insulin signaling cascades as well as stress-sensitive pathway , including IR,IRS1/2, PKB, GSK3β, FOXO, and JNK in rat liver. Our study demonstrated melatonin canprotect L02 cells treated with FFA and rats fed with high fat diet against high-lipid-inducedinsulin resistance in vitro and in vivo.
引文
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