姜黄素对2型糖尿病大鼠骨骼肌胰岛素抵抗的作用及机制研究
摘要
目的：姜黄素是一种天然多酚类化合物。研究表明，姜黄素能够降低2型糖尿病大鼠的血糖、血脂，增加机体葡萄糖稳态。骨骼肌胰岛素抵抗是2型糖尿病的主要病理特征。目前对于姜黄素是否能够改善骨骼肌胰岛素抵抗还未见报道。本课题以2型糖尿病大鼠和胰岛素抵抗L6骨骼肌细胞为模型，探讨姜黄素对2型糖尿病大鼠骨骼肌胰岛素抵抗的作用及机制。
方法：体内实验：100只雄性Wistar大鼠随机分为2组，一组为空白对照组（10只），另一组为2型糖尿病造模组（90只），采用小剂量链脲佐菌素（30mg/kgBW）联合高脂高糖饲料诱导2型糖尿病模型。模型成功后，将符合标准的2型糖尿病大鼠随机分为4组：糖尿病模型组、姜黄素低剂量组（50mg/kg BW）、姜黄素中剂量组（150mg/kg BW）和姜黄素高剂量组（250mg/kg BW）。给予姜黄素干预45天后，检测空腹血糖、血脂、血清胰岛素、游离脂肪酸等指标；采用Western blot方法检测大鼠骨骼肌调节葡萄糖和脂肪酸代谢相关蛋白的表达情况。体外实验：将L6骨骼肌细胞分为对照组、胰岛素抵抗组和姜黄素处理组。对照组为正常细胞；胰岛素抵抗组用0.25mmol/L软脂酸诱导24h建立胰岛素抵抗模型；姜黄素处理组细胞分别用5μmol/L、10μmol/L、20μmol/L和40μmol/L姜黄素与0.25mmol/L软脂酸共同孵育24h。采用3H标记葡萄糖摄取实验检测细胞对葡萄糖的摄取能力；应用GS-MS检测细胞培养液中软脂酸的浓度；采用Western blot方法测定细胞内参与葡萄糖和脂肪酸代谢调节的蛋白的表达变化。
结果：体内实验：与糖尿病模型组相比，姜黄素各干预组大鼠空腹血糖、血脂、血清游离脂肪酸水平显著降低，血清胰岛素水平显著升高；姜黄素能够显著促进2型糖尿病大鼠骨骼肌AMP激活的蛋白激酶（AMPK）的磷酸化，增加了细胞膜脂肪酸转位酶FAT/CD36、线粒体肉碱棕榈酰转移酶-（CPT1）和中链酯酰辅酶A脱氢酶（MCAD）的表达，抑制了糖原合成酶（GS）的磷酸化和丙酮酸脱氢酶激酶4（PDK4）的蛋白表达。体外实验：姜黄素在10μmol/L及以上的剂量显著增加了胰岛素抵抗L6骨骼肌细胞对3H标记的葡萄糖的摄取；姜黄素降低了胰岛素抵抗的L6骨骼肌细胞培养液中软脂酸的浓度；姜黄素促进了胰岛素抵抗的L6骨骼肌细胞内LKB1、AMPK和乙酰辅酶A羧化酶（ACC）的磷酸化水平，增加了过氧化物增殖物活化受体α（PPARα）、CPT1、MCAD和细胞膜FAT/CD36和葡萄糖转运蛋白4(GLUT4)的表达，抑制了GS的磷酸化和PDK4的蛋白表达；AMPK抑制剂——化合物C抑制了姜黄素对胰岛素抵抗L6骨骼肌细胞中AMPK及下游分子的作用；LKB1抑制剂——根赤壳菌素抑制了姜黄素对胰岛素抵抗L6骨骼肌细胞中LKB1及下游分子的作用。
结论：姜黄素能够显著降低2型糖尿病大鼠血糖、血脂的水平，增加胰岛素敏感性；姜黄素可以增加2型糖尿病大鼠骨骼肌内葡萄糖的氧化利用和糖原合成；姜黄素增加了2型糖尿病大鼠骨骼肌对脂肪酸的氧化利用，抑制了骨骼肌内脂类的堆积；姜黄素改善骨骼肌胰岛素抵抗可能是通过LKB1-AMPK介导的信号通路实现的。
Objective: Curcumin is a natural polyphenol compound. Curcumin has beenreported to lower plasma lipids and glucose and to increase glucose homeostasis intype2diabetic animals. Muscular insulin resistance is an important feature of type2diabetes. However, it is unclear whether curcumin can improve muscular insulinresistance. We conducted the present study to determine the effect of curcumin onmuscular insulin resistance as well as the mechanism by looking into its effects onlipid and glucose metabolism in skeletal muscle of type2diabetic rats and L6insulin-resistant myotubes.
Methods: In vivo experiment:100male wistar rats were divided into two groups,10were used as control, the other90were used to develop type2diabetes by lowdose STZ (30mg/kg) injection intraperitoneally combined with high fat diet. Afterdiabetic model established, the diabetic rats were divided into diabetic group, low(50mg/kg BW), medium (150mg/kg BW) and high (250mg/kg BW) doses ofcurcumin intervention groups. Curcumin intervention lasted for45days. Fastingblood glucose, lipids, serum insulin were measured; enzymes involve in fatty acidsand glucose metabolism in skeletal muscle were detected by Western blot. In vitroexperiment: L6myotubes were divided into control group, insulin resistant group andcurcumin treatment groups. Myotubes in control group were normal. Myotubes ininsulin resistant group were incubated with0.25mmol/L palmitate for24h. Myotubesin curcumin treatment groups were incubated with5μmol/L,10μmol/L,20μmol/L and40μmol/L curcumin in the presence of0.25mmol/L palmitate for24h. Glucose uptake by myotubes was measured using2-deoxy-[3H] D-glucose; palmitate concentration intne medium was determined by GS-MS; the expression of proteins regulating glucoseand fatty acids metabolism were detected by Western blot.
Results: In vivo experiment: curcumin significantly decreased blood glucose,lipids, serum FFAs and increased serum insulin; curcumin up-regulated expression ofphosphorylated AMPK, membrane FAT/CD36, mitochondrial CPT1and MCAD, butdown-regulated expression of PDK4and phosphorylated GS. In vitro experiment:curcumin at10μmol/L was adequate to cause a significant increase in2-deoxy-[3H]D-glucose uptake by L6myotubes; palmitate concentration in themedium of curcumin-treated L6myotubes was lower than that of insulin-resistantmyotubes; curcumin up-regulated expression of phosphorylated LKB1,phosphorylated AMPK, phosphorylated ACC, PPARα, CPT1, MCAD, FAT/CD36andGLUT4, but down-regulated expression of PDK4and phosphorylated GS ininsulin-resistant L6myotubes; the effects of curcumin on AMPK and downstreammolecules were suppressed by AMPK inhibitor, Compound C; LKB1, an upstreamkinase of AMPK, was activated by curcumin and inhibited together with AMPK anddownstream molecules by radicicol, an LKB1destabilizer.
Conclusion: Curcumin lowers blood glucose, lipids and imprvoes insulinsensitivity in type2diabetic rats; curcumin enhances glucose oxidation and glycogensynthesis in insulin-resistant skeletal muscle; curcumin increases fatty acids βoxidation and inhibits lipids accumulation in insulin-resistant skeletal muscle;curcumin plays its anti-insulin resistance role, at least in part, through LKB1-AMPKpathway.
方法：体内实验：100只雄性Wistar大鼠随机分为2组，一组为空白对照组（10只），另一组为2型糖尿病造模组（90只），采用小剂量链脲佐菌素（30mg/kgBW）联合高脂高糖饲料诱导2型糖尿病模型。模型成功后，将符合标准的2型糖尿病大鼠随机分为4组：糖尿病模型组、姜黄素低剂量组（50mg/kg BW）、姜黄素中剂量组（150mg/kg BW）和姜黄素高剂量组（250mg/kg BW）。给予姜黄素干预45天后，检测空腹血糖、血脂、血清胰岛素、游离脂肪酸等指标；采用Western blot方法检测大鼠骨骼肌调节葡萄糖和脂肪酸代谢相关蛋白的表达情况。体外实验：将L6骨骼肌细胞分为对照组、胰岛素抵抗组和姜黄素处理组。对照组为正常细胞；胰岛素抵抗组用0.25mmol/L软脂酸诱导24h建立胰岛素抵抗模型；姜黄素处理组细胞分别用5μmol/L、10μmol/L、20μmol/L和40μmol/L姜黄素与0.25mmol/L软脂酸共同孵育24h。采用3H标记葡萄糖摄取实验检测细胞对葡萄糖的摄取能力；应用GS-MS检测细胞培养液中软脂酸的浓度；采用Western blot方法测定细胞内参与葡萄糖和脂肪酸代谢调节的蛋白的表达变化。
结果：体内实验：与糖尿病模型组相比，姜黄素各干预组大鼠空腹血糖、血脂、血清游离脂肪酸水平显著降低，血清胰岛素水平显著升高；姜黄素能够显著促进2型糖尿病大鼠骨骼肌AMP激活的蛋白激酶（AMPK）的磷酸化，增加了细胞膜脂肪酸转位酶FAT/CD36、线粒体肉碱棕榈酰转移酶-（CPT1）和中链酯酰辅酶A脱氢酶（MCAD）的表达，抑制了糖原合成酶（GS）的磷酸化和丙酮酸脱氢酶激酶4（PDK4）的蛋白表达。体外实验：姜黄素在10μmol/L及以上的剂量显著增加了胰岛素抵抗L6骨骼肌细胞对3H标记的葡萄糖的摄取；姜黄素降低了胰岛素抵抗的L6骨骼肌细胞培养液中软脂酸的浓度；姜黄素促进了胰岛素抵抗的L6骨骼肌细胞内LKB1、AMPK和乙酰辅酶A羧化酶（ACC）的磷酸化水平，增加了过氧化物增殖物活化受体α（PPARα）、CPT1、MCAD和细胞膜FAT/CD36和葡萄糖转运蛋白4(GLUT4)的表达，抑制了GS的磷酸化和PDK4的蛋白表达；AMPK抑制剂——化合物C抑制了姜黄素对胰岛素抵抗L6骨骼肌细胞中AMPK及下游分子的作用；LKB1抑制剂——根赤壳菌素抑制了姜黄素对胰岛素抵抗L6骨骼肌细胞中LKB1及下游分子的作用。
结论：姜黄素能够显著降低2型糖尿病大鼠血糖、血脂的水平，增加胰岛素敏感性；姜黄素可以增加2型糖尿病大鼠骨骼肌内葡萄糖的氧化利用和糖原合成；姜黄素增加了2型糖尿病大鼠骨骼肌对脂肪酸的氧化利用，抑制了骨骼肌内脂类的堆积；姜黄素改善骨骼肌胰岛素抵抗可能是通过LKB1-AMPK介导的信号通路实现的。
Objective: Curcumin is a natural polyphenol compound. Curcumin has beenreported to lower plasma lipids and glucose and to increase glucose homeostasis intype2diabetic animals. Muscular insulin resistance is an important feature of type2diabetes. However, it is unclear whether curcumin can improve muscular insulinresistance. We conducted the present study to determine the effect of curcumin onmuscular insulin resistance as well as the mechanism by looking into its effects onlipid and glucose metabolism in skeletal muscle of type2diabetic rats and L6insulin-resistant myotubes.
Methods: In vivo experiment:100male wistar rats were divided into two groups,10were used as control, the other90were used to develop type2diabetes by lowdose STZ (30mg/kg) injection intraperitoneally combined with high fat diet. Afterdiabetic model established, the diabetic rats were divided into diabetic group, low(50mg/kg BW), medium (150mg/kg BW) and high (250mg/kg BW) doses ofcurcumin intervention groups. Curcumin intervention lasted for45days. Fastingblood glucose, lipids, serum insulin were measured; enzymes involve in fatty acidsand glucose metabolism in skeletal muscle were detected by Western blot. In vitroexperiment: L6myotubes were divided into control group, insulin resistant group andcurcumin treatment groups. Myotubes in control group were normal. Myotubes ininsulin resistant group were incubated with0.25mmol/L palmitate for24h. Myotubesin curcumin treatment groups were incubated with5μmol/L,10μmol/L,20μmol/L and40μmol/L curcumin in the presence of0.25mmol/L palmitate for24h. Glucose uptake by myotubes was measured using2-deoxy-[3H] D-glucose; palmitate concentration intne medium was determined by GS-MS; the expression of proteins regulating glucoseand fatty acids metabolism were detected by Western blot.
Results: In vivo experiment: curcumin significantly decreased blood glucose,lipids, serum FFAs and increased serum insulin; curcumin up-regulated expression ofphosphorylated AMPK, membrane FAT/CD36, mitochondrial CPT1and MCAD, butdown-regulated expression of PDK4and phosphorylated GS. In vitro experiment:curcumin at10μmol/L was adequate to cause a significant increase in2-deoxy-[3H]D-glucose uptake by L6myotubes; palmitate concentration in themedium of curcumin-treated L6myotubes was lower than that of insulin-resistantmyotubes; curcumin up-regulated expression of phosphorylated LKB1,phosphorylated AMPK, phosphorylated ACC, PPARα, CPT1, MCAD, FAT/CD36andGLUT4, but down-regulated expression of PDK4and phosphorylated GS ininsulin-resistant L6myotubes; the effects of curcumin on AMPK and downstreammolecules were suppressed by AMPK inhibitor, Compound C; LKB1, an upstreamkinase of AMPK, was activated by curcumin and inhibited together with AMPK anddownstream molecules by radicicol, an LKB1destabilizer.
Conclusion: Curcumin lowers blood glucose, lipids and imprvoes insulinsensitivity in type2diabetic rats; curcumin enhances glucose oxidation and glycogensynthesis in insulin-resistant skeletal muscle; curcumin increases fatty acids βoxidation and inhibits lipids accumulation in insulin-resistant skeletal muscle;curcumin plays its anti-insulin resistance role, at least in part, through LKB1-AMPKpathway.
引文
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