预防性补充维生素E和镁对糖尿病大鼠糖脂代谢的影响及机制研究
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摘要
糖尿病(DM)是一组病因和发病机理尚未完全阐明的内分泌代谢性疾病,表现为糖、脂肪、蛋白质代谢紊乱和继发水、电解质失衡,进而导致一系列并发症出现的综合病征。大量研究表明糖尿病的发生发展与肥胖、体内氧化与抗氧化水平改变及低血镁密切相关。以往研究表明单纯补充维生素E(VE)或镁对糖尿病有改善作用,但有关与糖尿病高危险因素同时预防性联合补充VE和镁对糖尿病糖脂代谢,尤其是胰岛素传导通路中信号分子影响的报导到目前为止在国内外尚属空白。本研究的目的就是观察预防性与危险因素同时补充VE联合镁对高脂高糖饮食和链脲咗菌素（STZ)诱导糖尿病大鼠氧化与抗氧化水平及糖脂代谢,特别是胰岛素传导通路中信号分子的影响。
Wistar大鼠适应性喂养1周后随机分为6组,均喂食高脂高糖饲料,其中模型对照组(C,n=15)仅喂食高脂高糖饲料、维生素E组(E,n=17)添加维生素E(VE)0.5g/kg饲料,中剂量镁组(MM,n=16)添加镁0.6g/kg饲料,高剂量镁组(HM,n=16)添加镁1.2g/kg饲料,维生素E+中剂量镁组(EMM,n=17)添加VE 0.5g/kg饲料和镁0.6g/kg饲料,维生素E+高剂量镁组(EHM,n=17)添加VE 0.5g/kg饲料和镁1.2g/kg饲料。各组大鼠喂食不同饲料4周并禁食24小时后,腹腔注射STZ诱导糖尿病模型。各组大鼠继续用不同饲料喂养4周,于宰杀前24小时禁食,水合氯醛麻醉后经腹主动脉抽取全血,分离肝脏、心脏、脾脏、胸腺和后肢骨骼肌备用。酶生化法测定肝脏丙二醛(MDA)含量和谷胱甘肽过氧化物酶(GSH-PX)及超氧化物歧化酶(SOD)活性;MTT法观察淋巴细胞增殖活性;H2O2诱导氧化溶血试验测定红细胞溶血度;全自动生化分析仪检测血浆总胆固醇(TC)、甘油三酯、高密度脂蛋白(HDL)和低密度脂蛋白(LDL)水平;血流变锥板粘度计检测低切、中切和高切血粘度;称重法计算心脏、肝脏、脾脏和胸腺指数;HE染色观察肝脏组织学改变;实时定量PCR观察骨骼肌胰岛素受体、葡萄糖转运蛋白-4(GLUT-4)mRNA的表达;免疫组织化学法检测骨骼肌胰岛素受体底物-1(IRS-1)的表达;Western blot检测腺苷酸活化蛋白激酶-α2(AMPK-α2)的蛋白表达;放射免疫法测定血清胰岛素、白介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)的水平;公式计算胰岛素抵抗水平。
结果发现:预防性补充VE或/和镁可以减轻糖尿病大鼠的胰岛素抵抗状态,与C组相比,胰岛素抵抗指数在E组、MM组、EMM组、EHM组分别降低了5.52(P<0.05)、2.28、3.29、2.65。血清胰岛素水平在各处理组均较明显降低,其中以EMM组降低最为明显P<0.01。预防性补充VE或/和镁对空腹血糖的影响不大。与模型组7.79 mmol/L相比,血中TC的水平在E组、MM组,HM组,EMM组,和EHM组,TC分别降低了4.72 mmol/L(P=0.004),3.54 mmol/L(P=0.062),1.36 mmol/L(P=0.436),3.75 mmol/L(P=0.016),和3.49 mmol/L(P=0.050)。各组甘油三酯和HDL水平略有提高,但与C组相比没有统计学意义。与C组相比,VE及VE和镁联合应用的各组中,LDL水平下降明显,而单独补充镁组的LDL水平不但没有下降,反而略有上升。预防性补充VE或/和镁对低切血粘度没有影响,但可以显著降低中切和高切血粘度,与模型对照组相比,P<0.001。补充VE可以降低肝脏指数,其他没有统计学意义。HE染色发现,模型组肝脏细胞呈空泡状,胞内充满脂肪,细胞核被推到一边,几乎找不到正常的肝细胞,预防性补充或/VE和镁可以改善这种状况,VE联合镁的改善效果优于单纯补充VE或镁。预防性补充VE或联合补充VE和镁可以降低肝脏MDA含量,与C组相比,以VE补充的效果最为明显,MDA水平下降了8.98(P<0.01),其次为EMM组下降了7.84(P<0.05),和EHM组7.56(P<0.05)。单纯补充镁对肝脏MDA水平没有影响。GSH-PX的活性在HM组得到显著提高(P<0.01),其次为EHM,和EMM组(P<0.05),余两组虽有提高但与对照组相比没有统计学意义。另外,与C组相比,单独或联合补充VE和镁均可以显著提高肝脏SOD活性(all P<0.05),以EHM组提高的最为明显。单纯或联合补充VE和镁可以适当提高淋巴细胞增殖活性,但统计学意义不大。预防性补充VE或/和镁,可以显著降低DM的红细胞溶血度(all P <0.05),下降幅度在各组分别为:E,0.19(P=0.003);MM,0.22(P=0.001);HM,0.17(P=0.030);EMM,0.25(P=0.001)和EHM,0.25(P=0.001)。与模型对照组相比,E, MM, HM,EMM和EHM饮食均可显著提高胰岛素受体和GLUT-4 mRNA的表达(all P<0.05);联合补充VE和中剂量镁可以提高IRS-1的表达,提高幅度为1.30(P=0.006);与C组相比,AMPK-α2的蛋白表达水平在各处理组均有显著提高(P<0.01),其中以EMM补充效果最好(P<0.001)。补充VE或/和镁对血清IL-6和TNF-α水平的影响与对照组相比没有显著性。析因分析结果表明VE和镁在各检测指标中不存在交互作用。
本研究结果表明,与糖尿病高危因素同时预防性补充VE或/和镁可以降低大鼠的胰岛素抵抗、TC、LDL和中高切血粘度水平,改善糖尿病大鼠的糖脂代谢,其机制与预防性补充VE或/和镁抑制大鼠脂质过氧化反应、增强抗氧化物酶活性和上调胰岛素信号传导通路中信号分子的表达有关。本研究为VE和镁将来在人群中的预防性应用奠定了一定的实验基础。
Diabetes is a group of endocrinological metabolic diseases whose etiology and pathogenesis have not yet been fully understood, expressed as glucose, lipids and protein metabolism disorders and secondary water, electrolyte imbalance, which led to a series of complications. Large number of studies show that the occurrence and development of diabetes are closely related to obesity, in vivo oxidation and antioxidant level changes and magnesium deficiency. Previous studies showed that supplement of vitamin E (VE) or magnesium had benificial effects on diabetes, but no documents reported the impacts of prophylactic supplementation of VE or/and magnesium on metabolism of glucose and lipids, especially insulin signaling pathway markers in diabetes while the high risk of diabetes happened at the same time. This study is a new finding to previous studies and the aims are to observe the effects of preventive treatment of VE or/and magnesium on glucose and lipid metabolism, the insulin signaling pathway molecules in high fat and high glucose diet and streptozotocin-induced diabetic rats.
Wistar rats were randomly assigned to six groups, all fed with high fat and glucose diets plus either 0.5 g/kg diet vitamin E (group E), 0.6 g/kg diet magnesium (group MM), 1.2 g/kg diet magnesium (group HM), 0.5 g/kg diet vitamin E plus 0.6 g/kg diet magnesium (group EMM), 0.5 g/kg diet vitamin E plus 1.2 g/kg diet magnesium (group EHM), or no supplement (group C). Four weeks treatment of different diets and an overnight empty stomach later, all rats were injected streptozotocin to provoke diabetes mellitus. The whole trial lasted eight weeks. Malondialdehyde (MDA) level, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were detected using enzyme-biochamical methods. Lymphocytes proliferative capacity was evaluated by MTT assay. Hemolytic degree of red blood cell were detected using hemolysis test. Total plasma cholesterol (TC), triglycerides, high density lipoprotein (HDL), and low density lipoprotein (LDL) were measured by automatic biochemistry analyzer. Blood viscosity was measured using cone viscometer. Histological changes of liver was examined by hematoxylin & eosin stain. mRNA expressions of insulin receptor and glucose transporter-4 (GLUT-4) of skeletal muscle were determined using quantitive real-time PCR. Insulin receptor substrate-1 (IRS-1) was detected by immunohistological method. Protein expression of AMP-activated protein kinase-α2 (AMPK-α2) was estimate by western blot. The serum concentration of insulin, interleukin-6 (IL-6), and tumor necrosis factor-α(TNF-α) were detected by radioimmunoassay; insulin resistance index was calculated by formula.
Compared with C group, insulin resistance index wad inhibited in E, MM, EMM, EHM group, the decrease was 5.52 (P<0.05), 2.28, 3.29, and 2.65 respectively. The insulin level decreased in all treated group, and the best effect was found in EMM group (P<0.01). No statistical difference was observed in fasting blood glucose in each treated group compared with control group. Compared with 7.79 mmol/L of TC in control group, the decrease of each treated group was 4.72 mmol/L (P=0.004); 3.54 mmol/L (P=0.062); 1.36 mmol/L (P=0.436); 3.75 mmol/L (P=0.016); 3.49 mmol/L (P=0.050) in E, MM, HM, EMM, and EHM group, respectively. Compared with C group, the differences of middle and high shear rates blood viscosity were lower in each treated groups (all P <0.001); but no significant changes were observed in low shear rate blood viscosity. Liver index in E group descended (P=0.034) while thymus index decreased in M and EM group (P=0.045, 0.035 respectively) compared with C group; no significant changes were founded in heart and spleen index. For histological changes of liver, hepatocytes were tumescent and filled with fat vacuole of inequality of size. The cell nuclei was pulled to the side by fat vacuole, and fatty infiltration was seen in the liver as a whole in control group. Prophylactic treatment of VE and magnesium could improve this status and the helpful effect in combined use of VE and magnesium was better than VE or magnesium supplementation alone. Prophylactic supplementation of VE or VE combined magnesium could attenuate the MDA level in liver, the decrease in E, EMM, and EHM group was 8.98 (P<0.01), 7.84 (P<0.05), and 7.56 (P<0.05) respectively. No benifical effect on MDA was observed in respective supplementation of magnesium alone. The activity of GSH-PX elevated in HM, EMM, and EHM group (P<0.05). SOD activity elevated in each treated group(all P<0.05). No statistical difference was observed on lymphocyte proliferation capacity between control group and each treated group. Preventive supplementation of VE or/and magnesium attenuated hemolytic degree of red blood cell greatly (all P <0.05), the decrease in each group was:E, 0.19 (P=0.003); MM, 0.22 (P=0.001); HM, 0.17 (P=0.030); EMM, 0.25 (P=0.001); and EHM, 0.25 (P=0.001), respectively. The mRNA expression of insulin receptor and GLUT-4 in E, MM, HM, EMM and EHM diet increased (all P<0.05). IRS-1 elevated 1.30 in EMM group (P=0.006), although elevation were observed in other treated groups, but no significant differences were observed compared with control group. Protein expression of AMPK-α2 increased in all treated group (P<0.01), and the best effect was supposed in EMM group (P<0.001). No significant difference were found in serum level of IL-6 and TNF-αin five treated group compared with control group. Statistical analysis showed there was no interaction between VE and magnesium.
In conclusion, the present study, at the first time, suggests that a preventive supplementation of VE or/and magnesium are beneficial to improve pathologic status of inslin resistance and lipid metabolism, the mechanism may be related to the inhibition of lipid peroxidation, increase of antioxidative level and up-regulation of insulin signaling pathway markers. The best effects were found in EMM group. This study provides a experimental basis for the preventive application of VE combined magnesium in crowd in the future.
Wistar大鼠适应性喂养1周后随机分为6组,均喂食高脂高糖饲料,其中模型对照组(C,n=15)仅喂食高脂高糖饲料、维生素E组(E,n=17)添加维生素E(VE)0.5g/kg饲料,中剂量镁组(MM,n=16)添加镁0.6g/kg饲料,高剂量镁组(HM,n=16)添加镁1.2g/kg饲料,维生素E+中剂量镁组(EMM,n=17)添加VE 0.5g/kg饲料和镁0.6g/kg饲料,维生素E+高剂量镁组(EHM,n=17)添加VE 0.5g/kg饲料和镁1.2g/kg饲料。各组大鼠喂食不同饲料4周并禁食24小时后,腹腔注射STZ诱导糖尿病模型。各组大鼠继续用不同饲料喂养4周,于宰杀前24小时禁食,水合氯醛麻醉后经腹主动脉抽取全血,分离肝脏、心脏、脾脏、胸腺和后肢骨骼肌备用。酶生化法测定肝脏丙二醛(MDA)含量和谷胱甘肽过氧化物酶(GSH-PX)及超氧化物歧化酶(SOD)活性;MTT法观察淋巴细胞增殖活性;H2O2诱导氧化溶血试验测定红细胞溶血度;全自动生化分析仪检测血浆总胆固醇(TC)、甘油三酯、高密度脂蛋白(HDL)和低密度脂蛋白(LDL)水平;血流变锥板粘度计检测低切、中切和高切血粘度;称重法计算心脏、肝脏、脾脏和胸腺指数;HE染色观察肝脏组织学改变;实时定量PCR观察骨骼肌胰岛素受体、葡萄糖转运蛋白-4(GLUT-4)mRNA的表达;免疫组织化学法检测骨骼肌胰岛素受体底物-1(IRS-1)的表达;Western blot检测腺苷酸活化蛋白激酶-α2(AMPK-α2)的蛋白表达;放射免疫法测定血清胰岛素、白介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)的水平;公式计算胰岛素抵抗水平。
结果发现:预防性补充VE或/和镁可以减轻糖尿病大鼠的胰岛素抵抗状态,与C组相比,胰岛素抵抗指数在E组、MM组、EMM组、EHM组分别降低了5.52(P<0.05)、2.28、3.29、2.65。血清胰岛素水平在各处理组均较明显降低,其中以EMM组降低最为明显P<0.01。预防性补充VE或/和镁对空腹血糖的影响不大。与模型组7.79 mmol/L相比,血中TC的水平在E组、MM组,HM组,EMM组,和EHM组,TC分别降低了4.72 mmol/L(P=0.004),3.54 mmol/L(P=0.062),1.36 mmol/L(P=0.436),3.75 mmol/L(P=0.016),和3.49 mmol/L(P=0.050)。各组甘油三酯和HDL水平略有提高,但与C组相比没有统计学意义。与C组相比,VE及VE和镁联合应用的各组中,LDL水平下降明显,而单独补充镁组的LDL水平不但没有下降,反而略有上升。预防性补充VE或/和镁对低切血粘度没有影响,但可以显著降低中切和高切血粘度,与模型对照组相比,P<0.001。补充VE可以降低肝脏指数,其他没有统计学意义。HE染色发现,模型组肝脏细胞呈空泡状,胞内充满脂肪,细胞核被推到一边,几乎找不到正常的肝细胞,预防性补充或/VE和镁可以改善这种状况,VE联合镁的改善效果优于单纯补充VE或镁。预防性补充VE或联合补充VE和镁可以降低肝脏MDA含量,与C组相比,以VE补充的效果最为明显,MDA水平下降了8.98(P<0.01),其次为EMM组下降了7.84(P<0.05),和EHM组7.56(P<0.05)。单纯补充镁对肝脏MDA水平没有影响。GSH-PX的活性在HM组得到显著提高(P<0.01),其次为EHM,和EMM组(P<0.05),余两组虽有提高但与对照组相比没有统计学意义。另外,与C组相比,单独或联合补充VE和镁均可以显著提高肝脏SOD活性(all P<0.05),以EHM组提高的最为明显。单纯或联合补充VE和镁可以适当提高淋巴细胞增殖活性,但统计学意义不大。预防性补充VE或/和镁,可以显著降低DM的红细胞溶血度(all P <0.05),下降幅度在各组分别为:E,0.19(P=0.003);MM,0.22(P=0.001);HM,0.17(P=0.030);EMM,0.25(P=0.001)和EHM,0.25(P=0.001)。与模型对照组相比,E, MM, HM,EMM和EHM饮食均可显著提高胰岛素受体和GLUT-4 mRNA的表达(all P<0.05);联合补充VE和中剂量镁可以提高IRS-1的表达,提高幅度为1.30(P=0.006);与C组相比,AMPK-α2的蛋白表达水平在各处理组均有显著提高(P<0.01),其中以EMM补充效果最好(P<0.001)。补充VE或/和镁对血清IL-6和TNF-α水平的影响与对照组相比没有显著性。析因分析结果表明VE和镁在各检测指标中不存在交互作用。
本研究结果表明,与糖尿病高危因素同时预防性补充VE或/和镁可以降低大鼠的胰岛素抵抗、TC、LDL和中高切血粘度水平,改善糖尿病大鼠的糖脂代谢,其机制与预防性补充VE或/和镁抑制大鼠脂质过氧化反应、增强抗氧化物酶活性和上调胰岛素信号传导通路中信号分子的表达有关。本研究为VE和镁将来在人群中的预防性应用奠定了一定的实验基础。
Diabetes is a group of endocrinological metabolic diseases whose etiology and pathogenesis have not yet been fully understood, expressed as glucose, lipids and protein metabolism disorders and secondary water, electrolyte imbalance, which led to a series of complications. Large number of studies show that the occurrence and development of diabetes are closely related to obesity, in vivo oxidation and antioxidant level changes and magnesium deficiency. Previous studies showed that supplement of vitamin E (VE) or magnesium had benificial effects on diabetes, but no documents reported the impacts of prophylactic supplementation of VE or/and magnesium on metabolism of glucose and lipids, especially insulin signaling pathway markers in diabetes while the high risk of diabetes happened at the same time. This study is a new finding to previous studies and the aims are to observe the effects of preventive treatment of VE or/and magnesium on glucose and lipid metabolism, the insulin signaling pathway molecules in high fat and high glucose diet and streptozotocin-induced diabetic rats.
Wistar rats were randomly assigned to six groups, all fed with high fat and glucose diets plus either 0.5 g/kg diet vitamin E (group E), 0.6 g/kg diet magnesium (group MM), 1.2 g/kg diet magnesium (group HM), 0.5 g/kg diet vitamin E plus 0.6 g/kg diet magnesium (group EMM), 0.5 g/kg diet vitamin E plus 1.2 g/kg diet magnesium (group EHM), or no supplement (group C). Four weeks treatment of different diets and an overnight empty stomach later, all rats were injected streptozotocin to provoke diabetes mellitus. The whole trial lasted eight weeks. Malondialdehyde (MDA) level, superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were detected using enzyme-biochamical methods. Lymphocytes proliferative capacity was evaluated by MTT assay. Hemolytic degree of red blood cell were detected using hemolysis test. Total plasma cholesterol (TC), triglycerides, high density lipoprotein (HDL), and low density lipoprotein (LDL) were measured by automatic biochemistry analyzer. Blood viscosity was measured using cone viscometer. Histological changes of liver was examined by hematoxylin & eosin stain. mRNA expressions of insulin receptor and glucose transporter-4 (GLUT-4) of skeletal muscle were determined using quantitive real-time PCR. Insulin receptor substrate-1 (IRS-1) was detected by immunohistological method. Protein expression of AMP-activated protein kinase-α2 (AMPK-α2) was estimate by western blot. The serum concentration of insulin, interleukin-6 (IL-6), and tumor necrosis factor-α(TNF-α) were detected by radioimmunoassay; insulin resistance index was calculated by formula.
Compared with C group, insulin resistance index wad inhibited in E, MM, EMM, EHM group, the decrease was 5.52 (P<0.05), 2.28, 3.29, and 2.65 respectively. The insulin level decreased in all treated group, and the best effect was found in EMM group (P<0.01). No statistical difference was observed in fasting blood glucose in each treated group compared with control group. Compared with 7.79 mmol/L of TC in control group, the decrease of each treated group was 4.72 mmol/L (P=0.004); 3.54 mmol/L (P=0.062); 1.36 mmol/L (P=0.436); 3.75 mmol/L (P=0.016); 3.49 mmol/L (P=0.050) in E, MM, HM, EMM, and EHM group, respectively. Compared with C group, the differences of middle and high shear rates blood viscosity were lower in each treated groups (all P <0.001); but no significant changes were observed in low shear rate blood viscosity. Liver index in E group descended (P=0.034) while thymus index decreased in M and EM group (P=0.045, 0.035 respectively) compared with C group; no significant changes were founded in heart and spleen index. For histological changes of liver, hepatocytes were tumescent and filled with fat vacuole of inequality of size. The cell nuclei was pulled to the side by fat vacuole, and fatty infiltration was seen in the liver as a whole in control group. Prophylactic treatment of VE and magnesium could improve this status and the helpful effect in combined use of VE and magnesium was better than VE or magnesium supplementation alone. Prophylactic supplementation of VE or VE combined magnesium could attenuate the MDA level in liver, the decrease in E, EMM, and EHM group was 8.98 (P<0.01), 7.84 (P<0.05), and 7.56 (P<0.05) respectively. No benifical effect on MDA was observed in respective supplementation of magnesium alone. The activity of GSH-PX elevated in HM, EMM, and EHM group (P<0.05). SOD activity elevated in each treated group(all P<0.05). No statistical difference was observed on lymphocyte proliferation capacity between control group and each treated group. Preventive supplementation of VE or/and magnesium attenuated hemolytic degree of red blood cell greatly (all P <0.05), the decrease in each group was:E, 0.19 (P=0.003); MM, 0.22 (P=0.001); HM, 0.17 (P=0.030); EMM, 0.25 (P=0.001); and EHM, 0.25 (P=0.001), respectively. The mRNA expression of insulin receptor and GLUT-4 in E, MM, HM, EMM and EHM diet increased (all P<0.05). IRS-1 elevated 1.30 in EMM group (P=0.006), although elevation were observed in other treated groups, but no significant differences were observed compared with control group. Protein expression of AMPK-α2 increased in all treated group (P<0.01), and the best effect was supposed in EMM group (P<0.001). No significant difference were found in serum level of IL-6 and TNF-αin five treated group compared with control group. Statistical analysis showed there was no interaction between VE and magnesium.
In conclusion, the present study, at the first time, suggests that a preventive supplementation of VE or/and magnesium are beneficial to improve pathologic status of inslin resistance and lipid metabolism, the mechanism may be related to the inhibition of lipid peroxidation, increase of antioxidative level and up-regulation of insulin signaling pathway markers. The best effects were found in EMM group. This study provides a experimental basis for the preventive application of VE combined magnesium in crowd in the future.
引文
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