| 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 conditionsHuman 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.
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