枸杞多糖对2型糖尿病大鼠胰岛素抵抗的作用及机制研究
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摘要
目的采用高脂高糖饲料喂养8周加小剂量链脲佐菌素(Streptozocin,STZ)腹腔注射的方法复制2型糖尿病大鼠模型,通过观察中药提取物枸杞多糖(lycium barbarum polysaccharides,LBP)对2型糖尿病大鼠糖、脂代谢紊乱及肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、骨骼肌组织胰岛素信号分子表达的影响,探讨其改善2型糖尿病大鼠胰岛素抵抗的作用及机制,为枸杞多糖治疗2型糖尿病的临床应用提供实验依据,也为进一步认识、研究、开发利用枸杞多糖提供理论依据。
方法将100只雄性SD大鼠随机分为正常对照组(20只)和造模组(80只)2组,并分别给予常规饲料和高脂高糖饲料喂养。8周后,造模组的大鼠腹腔注射链脲佐菌素(STZ)30mg/kg以诱导2型糖尿病大鼠模型。糖尿病大鼠成模后再随机分为5组:糖尿病模型组、高剂量LBP干预组、中剂量LBP干预组、低剂量LBP干预组及二甲双胍(Metformin,Met)干预组。高、中、低剂量LBP干预组及二甲双胍干预组的大鼠每只每日分别予以LBP160mg/kg、80mg/kg、40mg/kg及Met 250mg/kg灌胃(Intragastric,ig),正常对照组及糖尿病模型组的大鼠则每只每日予以等量的蒸馏水灌胃。造模成功时处死正常大鼠及糖尿病大鼠各6只,取血清测定空腹血糖、空腹胰岛素、TG及TC水平;计算胰岛素敏感指数(insulin sensitive index,ISI)及胰岛素抵抗指数(insulin resistance index,IRI);取胰腺组织行HE染色光镜观察。药物干预6周后,处死所有的动物,取血清测定空腹血糖、空腹胰岛素、TG、TC、游离脂肪酸(free fatty acid,FFA)及TNF-α水平;取后肢股四头肌组织,免疫组织化学方法检测骨骼肌组织胰岛素受体(Insulin receptor,InsR)和胰岛素受体底物-1(Insulin receptor substrate,IRS-1)的表达;电子显微镜观察骨骼肌组织超微结构的变化;取胰腺组织行HE染色光镜观察;计算ISI及IRI。
结果本实验采用高脂高糖饮食加小剂量STZ诱导的糖尿病大鼠血糖、血脂、IRI较正常对照组明显升高,ISI显著降低,胰岛β细胞部分损伤,符合2型糖尿病发病特点及生化特征。糖尿病模型组血糖、IRI、TG、TC、血清FFA及TNF-α水平较正常对照组明显升高(P<0.05,P<0.01),ISI及骨骼肌组织InsR、IRS-1表达水平显著降低(P<0.05,P<0.01),空腹胰岛素水平无统计学差异(P>0.05)。低剂量LBP干预组上述各指标与糖尿病模型组相比均无统计学差异(P>0.05)。中剂量LBP干预组血糖、IRI及TC水平较糖尿病模型组明显降低(P<0.05,P<0.01),ISI及骨骼肌组织InsR、IRS-1表达水平显著升高(P<0.05,P<0.01),空腹胰岛素、TG、血清FFA及TNF-α水平无统计学差异(P>0.05)。高剂量LBP干预组血糖、IRI、TC、及血清FFA水平较糖尿病模型组明显降低(P<0.05,P<0.01),ISI及骨骼肌组织InsR、IRS-1表达水平显著升高(P<0.05,P<0.01),空腹胰岛素、TG及血清TNF-α水平无统计学差异(P>0.05)。二甲双胍干预组血糖、IRI、血清FFA及TNF-α水平较糖尿病模型组明显降低(P<0.05,P<0.01),ISI及骨骼肌组织InsR、IRS-1表达水平显著升高(P<0.05,P<0.01),空腹胰岛素、TG及TC水平无统计学差异(P>0.05)。光镜下,糖尿病模型组大鼠胰岛形态欠规则,胰岛数及岛内分泌细胞数减少,胰岛萎缩,部分细胞空泡变性;低剂量LBP干预组大鼠胰腺病理改变程度仍较重,中剂量LBP干预组、高剂量LBP干预组及二甲双胍干预组大鼠胰腺病理改变程度较糖尿病模型组有所减轻。电镜下,糖尿病模型组大鼠骨骼肌细胞的部分肌原纤维排列紊乱,部分线粒体肿胀、空泡变性,可见嵴断裂、溶解,部分毛细血管内皮细胞肿胀伴管腔狭窄;各药物干预组大鼠骨骼肌超微结构改变的程度较糖尿病模型组有所减轻。
结论1、枸杞多糖能通过提高2型糖尿病大鼠的胰岛素敏感性,实现降低血糖的作用。2、枸杞多糖可能并不通过降低血清TNF-α水平,改善2型糖尿病大鼠的胰岛素抵抗。3、枸杞多糖可能通过纠正2型糖尿病大鼠脂代谢紊乱,减轻胰岛素信号转导障碍,实现改善胰岛素抵抗,降低血糖的作用。4、枸杞多糖对2型糖尿病大鼠的胰腺有一定的保护作用。
Objectives The model of type 2 diabetic rats was established by high-fat and high-sugar diet feeding for 8 weeks combined with the intravenous injection of a small dose of streptozotocin(STZ). The study is to investigate mechanism of lyceum barbarum polysaccharides(LBP)’s effect on improving insulin resistance of type 2 diabetic rats by observing its effects on glucose metabolism disorder, lipid metabolism disorder, tumor necrosis factor-α(TNF-α) and expressions of insulin signal molecules in skeletal muscle tissue of type 2 diabetic rats, which can provide experimental evidence of LBP curing type 2 diabetes mellitus and offer academic foundation to further understand, research, explore and make use of LBP.
Methods One hundred male SD rats were divided into two groups at random: the normal control group(twenty rats) and the induced model group(eighty rats). They were respectively fed with two sorts of different diets: chow diet and high-fat and high-sugar diet. After 8 weeks, rats in the induced model group were injected with a small dose of STZ (30mg/kg) into abdominal cavity to induce the model of type 2 diabetic rats. Then the diabetic rats were randomly assigned into 5 groups : the diabetic model group, the high dose of LBP group, the middle dose of LBP group, the low dose of LBP group and the metformin group. The high, middle, low dose of LBP group and the metformin group were respectively intragastric with LBP 160, 80, 40mg/kg and Met 250 mg/kg. The normal control group and the diabetic model group were fed with distilled water by oral administration method. When the diabetic rats were established, six rats from the normal control group and six rats from the diabetic model group were killed. Their serum were used to defect fasting blood glucose (FBG), fasting insulin(FINS), total cholesterol (TC) and triglyceride (TG). Insulin sensitive index (ISI) and insulin resistance index(IRI) were calculated. Their pancreas were treated by conventional dyeing with HE and observed with optical microscope. The course of treatment lasted for 6 weeks. When the treatment course was finished, all rats were sacrificed. Their serum were extracted for measuring FBG, FINS, TC, TG, free fatty acid(FFA) and TNF-α. The quadriceps femoris samples were collected. The espressions of insulin receptor (InsR) and insulin receptor substrate-1 (IRS-1) in the sketeal muscule tissue were examined by immunohistochemisty. The skelet muscule ultramicrostructure was observed by electron microscope. The pancreas were treated by conventional dyeing with HE and observed with optical microscope. We could calculate ISI and IRI.
Results The levels of blood glucose, blood lipid and IRI of the diabetic rats fed with high-fat-high-sugar and injected with a small dose STZ were markely increased as compared with those of the normal control group. ISI of the diabetic rats was reduced as compared with that of the normal control group. Their pancreasβcells were partly injured. Those accorded with the feature of type 2 diabetic pathogenesis and biochemistry. The levels of blood glucose, TG, TC, serum FFA, TNF-αand IRI in the diabetic model group were significantly higher than those in the normal control group (P<0.05, P<0.01). ISI and the expression levels of InsR and IRS-1 in the sketeal muscule tissue in the diabetic model group were markely lower than those in the normal control group (P<0.05, P<0.01). The level of fasting insulin was no significant difference between the diabetic model group and the normal control group (P>0.05). The aforementioned indexs were no significant difference between the diabetic model group and the low dose of LBP group (P>0.05). IRI, the levels of blood glucose and TC in the middle dose of LBP group were significantly lower than those in the diabetic model group(P<0.05, P<0.01). ISI, the expression levels of InsR and IRS-1 in the sketeal muscule tissue in the middle dose of LBP group were significantly higher than those in the diabetic model group (P<0.05, P<0.01). The levels of fasting insulin, TG, serum FFA and TNF-α were no significant difference between the diabetic model group and the middle dose of LBP group(P>0.05). IRI, the levels of blood glucose, TC and serum FFA in the high dose of LBP group were significantly lower than those in the diabetic model group (P<0.05, P<0.01). ISI and the expression levels of InsR and IRS-1 in the sketeal muscule tissue in the high dose of LBP group were significantly higher than those in the diabetic model group (P<0.05, P<0.01). The levels of fasting insulin, TG and serum TNF-αwere no significant difference between the diabetic model group and the high dose of LBP group (P>0.05). IRI and the levels of blood glucose, serum FFA and TNF-αin the metformin group were significantly lower than those in the diabetic model group (P<0.05, P<0.01). ISI and the expression levels of InsR and IRS-1 in the sketeal muscule tissue in the metformin group were significantly higher than those in the diabetic model group (P<0.05, P<0.01). The levels of fasting insulin, TG and TC were no significant difference between the diabetic model group and the metformin group(P>0.05). Under the optical microscopy, the islets’shape of rats in the diabetic model group was abnormity. The size and secretion cell number of rats’islets were reduced. The islets were atrophy. Some islets cells appeared vacuolation degeneration. Pathologic changes of rats’pancreas in the low dose of LBP group were still serious. Pathologic changes of rats’pancreas in the middle, high dose of LBP group and the metformin group were obviously alleviated. Under the electron microscopy, some of the muscle fibers of skeletal muscle cells ranked out of order in the diabetic model group. Some of mitochondrials were tumefaction, vacuolation degeneration and ridge structure presented as breakage and unclear. Some of capillary endothelial cells were tumefaction and lead to narrow of the lumen. The ultrastructural alterations of skeletal muscle in the medication group were lightened
Conclusions (1) LBP could decrease the level of blood glucose by increasing insulin sensitivity of type 2 diabetic rats. (2) LBP could improve insulin resistance of type 2 diabetic rats not by reducing the level of serum TNF-α. (3) LBP could ameliorate insulin resistande and decrease blood glucose by rectifing lipid metabolism disorder and lightening drawback of insulin signal transduction. (4) LBP has some effects of pancreas-protection of type 2 diabetic rats.
方法将100只雄性SD大鼠随机分为正常对照组(20只)和造模组(80只)2组,并分别给予常规饲料和高脂高糖饲料喂养。8周后,造模组的大鼠腹腔注射链脲佐菌素(STZ)30mg/kg以诱导2型糖尿病大鼠模型。糖尿病大鼠成模后再随机分为5组:糖尿病模型组、高剂量LBP干预组、中剂量LBP干预组、低剂量LBP干预组及二甲双胍(Metformin,Met)干预组。高、中、低剂量LBP干预组及二甲双胍干预组的大鼠每只每日分别予以LBP160mg/kg、80mg/kg、40mg/kg及Met 250mg/kg灌胃(Intragastric,ig),正常对照组及糖尿病模型组的大鼠则每只每日予以等量的蒸馏水灌胃。造模成功时处死正常大鼠及糖尿病大鼠各6只,取血清测定空腹血糖、空腹胰岛素、TG及TC水平;计算胰岛素敏感指数(insulin sensitive index,ISI)及胰岛素抵抗指数(insulin resistance index,IRI);取胰腺组织行HE染色光镜观察。药物干预6周后,处死所有的动物,取血清测定空腹血糖、空腹胰岛素、TG、TC、游离脂肪酸(free fatty acid,FFA)及TNF-α水平;取后肢股四头肌组织,免疫组织化学方法检测骨骼肌组织胰岛素受体(Insulin receptor,InsR)和胰岛素受体底物-1(Insulin receptor substrate,IRS-1)的表达;电子显微镜观察骨骼肌组织超微结构的变化;取胰腺组织行HE染色光镜观察;计算ISI及IRI。
结果本实验采用高脂高糖饮食加小剂量STZ诱导的糖尿病大鼠血糖、血脂、IRI较正常对照组明显升高,ISI显著降低,胰岛β细胞部分损伤,符合2型糖尿病发病特点及生化特征。糖尿病模型组血糖、IRI、TG、TC、血清FFA及TNF-α水平较正常对照组明显升高(P<0.05,P<0.01),ISI及骨骼肌组织InsR、IRS-1表达水平显著降低(P<0.05,P<0.01),空腹胰岛素水平无统计学差异(P>0.05)。低剂量LBP干预组上述各指标与糖尿病模型组相比均无统计学差异(P>0.05)。中剂量LBP干预组血糖、IRI及TC水平较糖尿病模型组明显降低(P<0.05,P<0.01),ISI及骨骼肌组织InsR、IRS-1表达水平显著升高(P<0.05,P<0.01),空腹胰岛素、TG、血清FFA及TNF-α水平无统计学差异(P>0.05)。高剂量LBP干预组血糖、IRI、TC、及血清FFA水平较糖尿病模型组明显降低(P<0.05,P<0.01),ISI及骨骼肌组织InsR、IRS-1表达水平显著升高(P<0.05,P<0.01),空腹胰岛素、TG及血清TNF-α水平无统计学差异(P>0.05)。二甲双胍干预组血糖、IRI、血清FFA及TNF-α水平较糖尿病模型组明显降低(P<0.05,P<0.01),ISI及骨骼肌组织InsR、IRS-1表达水平显著升高(P<0.05,P<0.01),空腹胰岛素、TG及TC水平无统计学差异(P>0.05)。光镜下,糖尿病模型组大鼠胰岛形态欠规则,胰岛数及岛内分泌细胞数减少,胰岛萎缩,部分细胞空泡变性;低剂量LBP干预组大鼠胰腺病理改变程度仍较重,中剂量LBP干预组、高剂量LBP干预组及二甲双胍干预组大鼠胰腺病理改变程度较糖尿病模型组有所减轻。电镜下,糖尿病模型组大鼠骨骼肌细胞的部分肌原纤维排列紊乱,部分线粒体肿胀、空泡变性,可见嵴断裂、溶解,部分毛细血管内皮细胞肿胀伴管腔狭窄;各药物干预组大鼠骨骼肌超微结构改变的程度较糖尿病模型组有所减轻。
结论1、枸杞多糖能通过提高2型糖尿病大鼠的胰岛素敏感性,实现降低血糖的作用。2、枸杞多糖可能并不通过降低血清TNF-α水平,改善2型糖尿病大鼠的胰岛素抵抗。3、枸杞多糖可能通过纠正2型糖尿病大鼠脂代谢紊乱,减轻胰岛素信号转导障碍,实现改善胰岛素抵抗,降低血糖的作用。4、枸杞多糖对2型糖尿病大鼠的胰腺有一定的保护作用。
Objectives The model of type 2 diabetic rats was established by high-fat and high-sugar diet feeding for 8 weeks combined with the intravenous injection of a small dose of streptozotocin(STZ). The study is to investigate mechanism of lyceum barbarum polysaccharides(LBP)’s effect on improving insulin resistance of type 2 diabetic rats by observing its effects on glucose metabolism disorder, lipid metabolism disorder, tumor necrosis factor-α(TNF-α) and expressions of insulin signal molecules in skeletal muscle tissue of type 2 diabetic rats, which can provide experimental evidence of LBP curing type 2 diabetes mellitus and offer academic foundation to further understand, research, explore and make use of LBP.
Methods One hundred male SD rats were divided into two groups at random: the normal control group(twenty rats) and the induced model group(eighty rats). They were respectively fed with two sorts of different diets: chow diet and high-fat and high-sugar diet. After 8 weeks, rats in the induced model group were injected with a small dose of STZ (30mg/kg) into abdominal cavity to induce the model of type 2 diabetic rats. Then the diabetic rats were randomly assigned into 5 groups : the diabetic model group, the high dose of LBP group, the middle dose of LBP group, the low dose of LBP group and the metformin group. The high, middle, low dose of LBP group and the metformin group were respectively intragastric with LBP 160, 80, 40mg/kg and Met 250 mg/kg. The normal control group and the diabetic model group were fed with distilled water by oral administration method. When the diabetic rats were established, six rats from the normal control group and six rats from the diabetic model group were killed. Their serum were used to defect fasting blood glucose (FBG), fasting insulin(FINS), total cholesterol (TC) and triglyceride (TG). Insulin sensitive index (ISI) and insulin resistance index(IRI) were calculated. Their pancreas were treated by conventional dyeing with HE and observed with optical microscope. The course of treatment lasted for 6 weeks. When the treatment course was finished, all rats were sacrificed. Their serum were extracted for measuring FBG, FINS, TC, TG, free fatty acid(FFA) and TNF-α. The quadriceps femoris samples were collected. The espressions of insulin receptor (InsR) and insulin receptor substrate-1 (IRS-1) in the sketeal muscule tissue were examined by immunohistochemisty. The skelet muscule ultramicrostructure was observed by electron microscope. The pancreas were treated by conventional dyeing with HE and observed with optical microscope. We could calculate ISI and IRI.
Results The levels of blood glucose, blood lipid and IRI of the diabetic rats fed with high-fat-high-sugar and injected with a small dose STZ were markely increased as compared with those of the normal control group. ISI of the diabetic rats was reduced as compared with that of the normal control group. Their pancreasβcells were partly injured. Those accorded with the feature of type 2 diabetic pathogenesis and biochemistry. The levels of blood glucose, TG, TC, serum FFA, TNF-αand IRI in the diabetic model group were significantly higher than those in the normal control group (P<0.05, P<0.01). ISI and the expression levels of InsR and IRS-1 in the sketeal muscule tissue in the diabetic model group were markely lower than those in the normal control group (P<0.05, P<0.01). The level of fasting insulin was no significant difference between the diabetic model group and the normal control group (P>0.05). The aforementioned indexs were no significant difference between the diabetic model group and the low dose of LBP group (P>0.05). IRI, the levels of blood glucose and TC in the middle dose of LBP group were significantly lower than those in the diabetic model group(P<0.05, P<0.01). ISI, the expression levels of InsR and IRS-1 in the sketeal muscule tissue in the middle dose of LBP group were significantly higher than those in the diabetic model group (P<0.05, P<0.01). The levels of fasting insulin, TG, serum FFA and TNF-α were no significant difference between the diabetic model group and the middle dose of LBP group(P>0.05). IRI, the levels of blood glucose, TC and serum FFA in the high dose of LBP group were significantly lower than those in the diabetic model group (P<0.05, P<0.01). ISI and the expression levels of InsR and IRS-1 in the sketeal muscule tissue in the high dose of LBP group were significantly higher than those in the diabetic model group (P<0.05, P<0.01). The levels of fasting insulin, TG and serum TNF-αwere no significant difference between the diabetic model group and the high dose of LBP group (P>0.05). IRI and the levels of blood glucose, serum FFA and TNF-αin the metformin group were significantly lower than those in the diabetic model group (P<0.05, P<0.01). ISI and the expression levels of InsR and IRS-1 in the sketeal muscule tissue in the metformin group were significantly higher than those in the diabetic model group (P<0.05, P<0.01). The levels of fasting insulin, TG and TC were no significant difference between the diabetic model group and the metformin group(P>0.05). Under the optical microscopy, the islets’shape of rats in the diabetic model group was abnormity. The size and secretion cell number of rats’islets were reduced. The islets were atrophy. Some islets cells appeared vacuolation degeneration. Pathologic changes of rats’pancreas in the low dose of LBP group were still serious. Pathologic changes of rats’pancreas in the middle, high dose of LBP group and the metformin group were obviously alleviated. Under the electron microscopy, some of the muscle fibers of skeletal muscle cells ranked out of order in the diabetic model group. Some of mitochondrials were tumefaction, vacuolation degeneration and ridge structure presented as breakage and unclear. Some of capillary endothelial cells were tumefaction and lead to narrow of the lumen. The ultrastructural alterations of skeletal muscle in the medication group were lightened
Conclusions (1) LBP could decrease the level of blood glucose by increasing insulin sensitivity of type 2 diabetic rats. (2) LBP could improve insulin resistance of type 2 diabetic rats not by reducing the level of serum TNF-α. (3) LBP could ameliorate insulin resistande and decrease blood glucose by rectifing lipid metabolism disorder and lightening drawback of insulin signal transduction. (4) LBP has some effects of pancreas-protection of type 2 diabetic rats.
引文
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