冬连胶囊改善2型糖尿病胰岛β细胞分泌功能的临床及实验研究
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摘要
随着全球社会老龄化的日益加速,糖尿病的发病率正在逐年增加,糖尿病己成为继肿瘤、心脑血管疾病之后发病率居第3位的慢性非传染性疾病。糖尿病,尤其是2型糖尿病是中老年人的常见病和多发病,防治糖尿病已成为当今愈来愈重要的课题之一。近年来,随着对胰岛β细胞生理、病理研究的深入,保护胰岛β细胞的分泌功能已在防治2型糖尿病中受到越来越多的重视。冬连胶囊由麦冬多糖与黄连生物碱配伍组成,是导师针对2型糖尿病阴虚燥热证型所创立的中药组分配伍制剂。本论文在既往工作的基础上,着重研究了冬连胶囊对胰岛β细胞分泌功能与胰岛局部内分泌环境的影响,并以此为切入点探讨冬连胶囊防治2型糖尿病的可能作用机制。
第一部分临床研究
目的:观察冬连胶囊对2型糖尿病阴虚燥热型患者胰岛β细胞基础分泌功能的影响。
方法:采用随机分组、单盲、平行对照给药的方法。收集符合纳入标准2型糖尿病患者90例,用随机数字表的方法随机分为2组,治疗组43例,对照组47例。以糖尿病教育结合生活方式干预为基础治疗。基础治疗2周后,比较两组一般资料,两组资料具有可比性。治疗组服用冬连胶囊,对照组服用二甲双胍。治疗8周。记录两组患者治疗前后的中医症候积分、血糖、血脂、胰岛素(INS)、C肽(C-P)、胰岛素抵抗指数(IRI)、稳态模型β细胞分泌指数(HBCI),以及血、尿常规、肝肾功能。治疗结束后,比较两种药物对各项测定指标的影响,比较两种药物的单项症状疗效、中医症候疗效、疾病总疗效间的差异,比较两种药物的不良反应情况。
结果:90例患者中,有83例最终纳入实验,其中治疗组40例,对照组43例。①治疗后,治疗组积分较治疗前降低,且低于对照组。②治疗后,治疗组空腹血糖及餐后2h血糖,均较治疗前下降。③治疗后,治疗组TC较治疗前下降。④治疗后,治疗组INS、C-P、HBCI都较治疗前提高,IRI较治疗前降低。⑤治疗后,冬连胶囊能明显改善患者单项临床症状。⑥治疗后,治疗组中医症候疗效总有效率、高于对照组。⑦治疗后,治疗组疾病总疗效与对照组差别无统计学意义。⑧两组治疗前后均做了肝、肾功能及血、尿常规检查,治疗后未出现异常,表明冬连胶囊无不良反应。
结论:冬连胶囊能有效改善临床症状,降低空腹血糖及餐后2h血糖,降低血清胆固醇含量,改善糖、脂代谢紊乱,提高INS、C-P的分泌,改善HBCI,降低IRI,有较好的单项症状疗效、中医症候疗效和疾病总疗效,无不良反应情况。但由于目前对胰岛β细胞分泌功能的临床评价指标,尚存有争议,我们仅从血糖、INS、C-P、HBCI方面对β细胞的基础分泌功能进行了粗略的评价,本研究有待于实验部分筛选出中药组分配伍制剂改善胰岛β细胞分泌功能不同作用途径的特异性指标,进行多中心、大样本的深入研究,来进一步完善。
第二部分实验研究
目的:观察冬连胶囊对实验性2型糖尿病模型大鼠早期胰岛β细胞基础分泌功能的影响。
方法:将60只SD大鼠腹腔注射小剂量链脲菌素(STZ),配合给予高脂高糖饮食,建立模拟人类2型糖尿病模型,1周后,用随机数字表法分为模型组、冬连胶囊大剂量组、小剂量组和阳性对照药(二甲双胍)组、正常对照组。治疗4周后,观察体重、胰腺重量、血糖、血脂、肝功肾功的变化;观察血清胰岛素(INS)、C肽(C-P)、胰高血糖素(PG)、胰岛素样生长因子Ⅰ(IGFI)、IRI、HBCI的变化;观察胰岛HE染色切片、以及胰淀素、抵抗素的免疫组化切片。分析冬连胶囊改善胰岛β细胞分泌功能的可能作用机理。
结果:治疗4周后,正常组大鼠体毛纯白,有光亮泽,柔软清洁;造模各组大鼠毛色暗淡萎黄,体型消瘦。①冬连胶囊大剂量组大鼠体重和胰腺重量明显减轻,冬连胶囊小剂量组的体重也显著减轻。②胰岛HE染色:正常组大鼠胰岛岛型丰满,轮廓清晰,岛细胞分布均匀,排列较规则。模型组大鼠胰岛明显萎缩,总数量减少,胰岛细胞肥大、轮廓欠圆润,核呈梭状或不规则,部分细胞融合,出现玻璃样变性,可见β细胞空泡性变性。冬连胶囊大、小剂量组大鼠胰岛与腺体结合紧密,胰岛细胞较模型组多,呈圆或椭圆形,结构完整,细胞变性程度减轻。③模型组大鼠谷草转氨酶(AST)、谷丙转氨酶(ALT)、尿素(Urea)、肌酐(CRE)均较正常组升高。冬连胶囊大剂量组和二甲双胍组大鼠BUN、CRE比模型组降低,冬连胶囊小剂量组CRE比模型组下降。④模型组和正常组大鼠比较,总胆固醇(TC)、低密度脂蛋白(LDL-C)水平升高。冬连胶囊大、小剂量组和二甲双胍组与模型组比较,甘油三酯(TC)、TC/HDL降低。⑤模型组与正常组比较,空腹血糖(FBG)、INS、IRI升高,HBCI降低。冬连胶囊大、小剂量组和二甲双胍组与模型组比较,FBG、IRI降低。⑥模型组与正常组比较,PG、INS升高。冬连胶囊大、小剂量组和二甲双胍组与模型组比较,C-P、IGF_1升高。⑦模型组与正常组比较,IAPP表达面积比值升高。冬连胶囊大、小剂量组和二甲双胍组与模型组比较,IAPP表达面积比值升高。模型组与正常组比较,抵抗素表达面积比值降低。冬连胶囊大、二甲双胍组与模型组比较,抵抗素表达面积比值降低。
结论:①本实验采用STZ小剂量腹腔注射,配合高脂饲料喂养,成功诱导建立具有胰岛β细胞功能受损和胰岛素抵抗的病理特征的2型糖尿病模型。②冬连胶囊可改善大鼠的生存质量,对肝、肾功能无损害,对肾脏功能有保护作用。具有减轻大鼠体重,保护胰岛细胞的形态、功能的作用。③冬连胶囊能减少α细胞分泌PG,提高β细胞分泌C-P、INS、IAPP,减少抵抗素在胰岛细胞的表达,提高血清IGFⅠ水平,协调胰岛局部影响β细胞分泌功能各因素间的作用。④冬连胶囊保护、修复胰岛细胞,改善胰岛β细胞基础分泌功能的机理,可能与其减轻糖毒性、脂毒性,恢复胰岛细胞分泌激素间的反馈机制平衡,改善胰岛细胞自身的胰岛素抵抗有关。
Diabetes Mellitus,especially the the 2 type of Diabetes Mellitus is the common diseases in elderly people.Recently years,the study on theβ-cell function has attracted more and more concern.The Donglian capsule is made of Ophiopogonis Tuber Polysaccharide and rhizoma coptidis alkaloids,and just for the TCM syndrome type of yin deficiency inner heat.It can improve the glyeolipid metabolism disorder,prevent and treate Diabetic Complication of Blood Vessels,like Diabetic Nephropathy(DN) and Diabetic Retinopathy(DR).This paper is working on the base of the Previous studies,we observed the effects of the Donglian capsule onβ-cell function and local Endocrinal environment,and investigated its possible mechanisms.
PartⅠClinical research
Objective:Observing the effects ofβ-cell function made by the Donglian capsule on the 2TDM with yin deficiency inner heat.
Methods:The 90 2TDM with yin deficiency inner heat patients were divided into 2 groups randomly.The therapy group had 43 cases,treated with the Donglian capsule,the control group had 47 cases,treated with metformin hydrochloride.After two weeks basic treatment,the experiment lasted 8 weeks.Compare the effects with metformin hydrochloride,the indexs including liver function,kidney functions,blood glucose, blood lipid,insulin,c-peptide.Calculating the index of insulin resistance and the HomaβCell Function Index.Observing the preliminary situation of theβCell Function in 2DM patient with Donglian capsule.
Result:The Donglian capsule can improve the traditional Chinese medicine symptom efficacy,improve the disease effect,reducing the fasting blood glucose,2 hour postprandial blood glucose,reducing the Total Cholesterol,improving the lipid metabolicdisorder.Making theβcell secreted more insulin and c-peptide.
Conclusion:The Donglian capsule can improve clinical symptoms,reduce the blood glucose,reduce the TC,improve the blood glucose and lipid metabolism disorder, improve the level of INS,C-P and HBCI,reduce IRI.It has a better therapeutic effects.
PartⅡExperiment research
Objective:To investigate the effects of the combination of Ophiopogonis Tuber Polysaccharide with Rhizoma Coptidis Alkaloids(OP & RA,the donglian capsule) onβcell function in experimental diabetic rats.
Methods:The rats models of insulin resistance in 2 type diabetic were established by injecting low dose of streptozotocin(STZ) in 60 high fat-fed SD rats.After one week,the successful models were randomly divided into 4 groups:untreated group(n=7),high OPRA-treated group(n=9),low OPRA-treated group(n=8)and metformin-treated group(n=9),Meanwhile,a normal control group(n=10) was designed.After four weeks, the differences infasting blood glu-cose(FBG),serum lipid,pancreas glucagon(PG), insulin(INS),C piptide(C-P) and Insulin-Like Growth Factor I(IGF_I)were compared among the groups.The expressed area of the islet amyloid polypeptide(IAPP) and resistin, Homa-B Cell Function Index,the Insulin Resistance index are also be compared,too.
Results:The OPRA can significantly reduce the level of serum TC and fasting blood glucose,increase the serum insulin,C-P and HBCI,reduce the IRI,increse the IGFI, increse the expressed area of the IAPP,induce the the expressed area of the resistin.
Conclusion:The Combination of Ophiopogonis Tuber Polysaccharide with Rhizoma Coptidis Alkaloids can increase the secrete of insulin and reduce the secrete of PG.It can propect theβcell function,maybe through the way of alleviating the insulin resistance in pancreas islet,includingαandβcell.
第一部分临床研究
目的:观察冬连胶囊对2型糖尿病阴虚燥热型患者胰岛β细胞基础分泌功能的影响。
方法:采用随机分组、单盲、平行对照给药的方法。收集符合纳入标准2型糖尿病患者90例,用随机数字表的方法随机分为2组,治疗组43例,对照组47例。以糖尿病教育结合生活方式干预为基础治疗。基础治疗2周后,比较两组一般资料,两组资料具有可比性。治疗组服用冬连胶囊,对照组服用二甲双胍。治疗8周。记录两组患者治疗前后的中医症候积分、血糖、血脂、胰岛素(INS)、C肽(C-P)、胰岛素抵抗指数(IRI)、稳态模型β细胞分泌指数(HBCI),以及血、尿常规、肝肾功能。治疗结束后,比较两种药物对各项测定指标的影响,比较两种药物的单项症状疗效、中医症候疗效、疾病总疗效间的差异,比较两种药物的不良反应情况。
结果:90例患者中,有83例最终纳入实验,其中治疗组40例,对照组43例。①治疗后,治疗组积分较治疗前降低,且低于对照组。②治疗后,治疗组空腹血糖及餐后2h血糖,均较治疗前下降。③治疗后,治疗组TC较治疗前下降。④治疗后,治疗组INS、C-P、HBCI都较治疗前提高,IRI较治疗前降低。⑤治疗后,冬连胶囊能明显改善患者单项临床症状。⑥治疗后,治疗组中医症候疗效总有效率、高于对照组。⑦治疗后,治疗组疾病总疗效与对照组差别无统计学意义。⑧两组治疗前后均做了肝、肾功能及血、尿常规检查,治疗后未出现异常,表明冬连胶囊无不良反应。
结论:冬连胶囊能有效改善临床症状,降低空腹血糖及餐后2h血糖,降低血清胆固醇含量,改善糖、脂代谢紊乱,提高INS、C-P的分泌,改善HBCI,降低IRI,有较好的单项症状疗效、中医症候疗效和疾病总疗效,无不良反应情况。但由于目前对胰岛β细胞分泌功能的临床评价指标,尚存有争议,我们仅从血糖、INS、C-P、HBCI方面对β细胞的基础分泌功能进行了粗略的评价,本研究有待于实验部分筛选出中药组分配伍制剂改善胰岛β细胞分泌功能不同作用途径的特异性指标,进行多中心、大样本的深入研究,来进一步完善。
第二部分实验研究
目的:观察冬连胶囊对实验性2型糖尿病模型大鼠早期胰岛β细胞基础分泌功能的影响。
方法:将60只SD大鼠腹腔注射小剂量链脲菌素(STZ),配合给予高脂高糖饮食,建立模拟人类2型糖尿病模型,1周后,用随机数字表法分为模型组、冬连胶囊大剂量组、小剂量组和阳性对照药(二甲双胍)组、正常对照组。治疗4周后,观察体重、胰腺重量、血糖、血脂、肝功肾功的变化;观察血清胰岛素(INS)、C肽(C-P)、胰高血糖素(PG)、胰岛素样生长因子Ⅰ(IGFI)、IRI、HBCI的变化;观察胰岛HE染色切片、以及胰淀素、抵抗素的免疫组化切片。分析冬连胶囊改善胰岛β细胞分泌功能的可能作用机理。
结果:治疗4周后,正常组大鼠体毛纯白,有光亮泽,柔软清洁;造模各组大鼠毛色暗淡萎黄,体型消瘦。①冬连胶囊大剂量组大鼠体重和胰腺重量明显减轻,冬连胶囊小剂量组的体重也显著减轻。②胰岛HE染色:正常组大鼠胰岛岛型丰满,轮廓清晰,岛细胞分布均匀,排列较规则。模型组大鼠胰岛明显萎缩,总数量减少,胰岛细胞肥大、轮廓欠圆润,核呈梭状或不规则,部分细胞融合,出现玻璃样变性,可见β细胞空泡性变性。冬连胶囊大、小剂量组大鼠胰岛与腺体结合紧密,胰岛细胞较模型组多,呈圆或椭圆形,结构完整,细胞变性程度减轻。③模型组大鼠谷草转氨酶(AST)、谷丙转氨酶(ALT)、尿素(Urea)、肌酐(CRE)均较正常组升高。冬连胶囊大剂量组和二甲双胍组大鼠BUN、CRE比模型组降低,冬连胶囊小剂量组CRE比模型组下降。④模型组和正常组大鼠比较,总胆固醇(TC)、低密度脂蛋白(LDL-C)水平升高。冬连胶囊大、小剂量组和二甲双胍组与模型组比较,甘油三酯(TC)、TC/HDL降低。⑤模型组与正常组比较,空腹血糖(FBG)、INS、IRI升高,HBCI降低。冬连胶囊大、小剂量组和二甲双胍组与模型组比较,FBG、IRI降低。⑥模型组与正常组比较,PG、INS升高。冬连胶囊大、小剂量组和二甲双胍组与模型组比较,C-P、IGF_1升高。⑦模型组与正常组比较,IAPP表达面积比值升高。冬连胶囊大、小剂量组和二甲双胍组与模型组比较,IAPP表达面积比值升高。模型组与正常组比较,抵抗素表达面积比值降低。冬连胶囊大、二甲双胍组与模型组比较,抵抗素表达面积比值降低。
结论:①本实验采用STZ小剂量腹腔注射,配合高脂饲料喂养,成功诱导建立具有胰岛β细胞功能受损和胰岛素抵抗的病理特征的2型糖尿病模型。②冬连胶囊可改善大鼠的生存质量,对肝、肾功能无损害,对肾脏功能有保护作用。具有减轻大鼠体重,保护胰岛细胞的形态、功能的作用。③冬连胶囊能减少α细胞分泌PG,提高β细胞分泌C-P、INS、IAPP,减少抵抗素在胰岛细胞的表达,提高血清IGFⅠ水平,协调胰岛局部影响β细胞分泌功能各因素间的作用。④冬连胶囊保护、修复胰岛细胞,改善胰岛β细胞基础分泌功能的机理,可能与其减轻糖毒性、脂毒性,恢复胰岛细胞分泌激素间的反馈机制平衡,改善胰岛细胞自身的胰岛素抵抗有关。
Diabetes Mellitus,especially the the 2 type of Diabetes Mellitus is the common diseases in elderly people.Recently years,the study on theβ-cell function has attracted more and more concern.The Donglian capsule is made of Ophiopogonis Tuber Polysaccharide and rhizoma coptidis alkaloids,and just for the TCM syndrome type of yin deficiency inner heat.It can improve the glyeolipid metabolism disorder,prevent and treate Diabetic Complication of Blood Vessels,like Diabetic Nephropathy(DN) and Diabetic Retinopathy(DR).This paper is working on the base of the Previous studies,we observed the effects of the Donglian capsule onβ-cell function and local Endocrinal environment,and investigated its possible mechanisms.
PartⅠClinical research
Objective:Observing the effects ofβ-cell function made by the Donglian capsule on the 2TDM with yin deficiency inner heat.
Methods:The 90 2TDM with yin deficiency inner heat patients were divided into 2 groups randomly.The therapy group had 43 cases,treated with the Donglian capsule,the control group had 47 cases,treated with metformin hydrochloride.After two weeks basic treatment,the experiment lasted 8 weeks.Compare the effects with metformin hydrochloride,the indexs including liver function,kidney functions,blood glucose, blood lipid,insulin,c-peptide.Calculating the index of insulin resistance and the HomaβCell Function Index.Observing the preliminary situation of theβCell Function in 2DM patient with Donglian capsule.
Result:The Donglian capsule can improve the traditional Chinese medicine symptom efficacy,improve the disease effect,reducing the fasting blood glucose,2 hour postprandial blood glucose,reducing the Total Cholesterol,improving the lipid metabolicdisorder.Making theβcell secreted more insulin and c-peptide.
Conclusion:The Donglian capsule can improve clinical symptoms,reduce the blood glucose,reduce the TC,improve the blood glucose and lipid metabolism disorder, improve the level of INS,C-P and HBCI,reduce IRI.It has a better therapeutic effects.
PartⅡExperiment research
Objective:To investigate the effects of the combination of Ophiopogonis Tuber Polysaccharide with Rhizoma Coptidis Alkaloids(OP & RA,the donglian capsule) onβcell function in experimental diabetic rats.
Methods:The rats models of insulin resistance in 2 type diabetic were established by injecting low dose of streptozotocin(STZ) in 60 high fat-fed SD rats.After one week,the successful models were randomly divided into 4 groups:untreated group(n=7),high OPRA-treated group(n=9),low OPRA-treated group(n=8)and metformin-treated group(n=9),Meanwhile,a normal control group(n=10) was designed.After four weeks, the differences infasting blood glu-cose(FBG),serum lipid,pancreas glucagon(PG), insulin(INS),C piptide(C-P) and Insulin-Like Growth Factor I(IGF_I)were compared among the groups.The expressed area of the islet amyloid polypeptide(IAPP) and resistin, Homa-B Cell Function Index,the Insulin Resistance index are also be compared,too.
Results:The OPRA can significantly reduce the level of serum TC and fasting blood glucose,increase the serum insulin,C-P and HBCI,reduce the IRI,increse the IGFI, increse the expressed area of the IAPP,induce the the expressed area of the resistin.
Conclusion:The Combination of Ophiopogonis Tuber Polysaccharide with Rhizoma Coptidis Alkaloids can increase the secrete of insulin and reduce the secrete of PG.It can propect theβcell function,maybe through the way of alleviating the insulin resistance in pancreas islet,includingαandβcell.
引文
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