糖耐康干预糖耐量异常的临床研究和部分作用机制探讨
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摘要
本论文共分为文献综述、临床研究和实验研究三部分。
文献综述总结了中医药干预糖耐量异常的研究进展。首先总结了古今医家对IGT(脾瘅)病因病机的认识,接着分析了目前一些主要流行病学研究对IGT证型的认识,其后讨论了近年来中医药干预IGT的主要方法和进展,最后涉及了一些中医药研究IGT机制的内容。
临床部分即糖耐康颗粒治疗糖耐量异常的Ⅲ期临床试验,目的：进一步评价糖耐康颗粒治疗IGT的临床疗效及安全性。方法：采用多中心、随机、双盲、安慰剂平行对照设计,共480例受试者按3：1比例随机分入治疗组(糖耐康颗粒组)和对照组(安慰剂组),进行为期12周的干预。结果：用药12wk,治疗组餐后2小时血糖变化较对照组比较有统计学意义(P<0.05),治疗组优于对照组。给药12wk, FBS、FINS、2hINS与基线相比,两组无统计学差异,但HbAlc数据中治疗组较对照组有下降趋势。血脂观测指标在两组间均无显著差异。中医证候积分差异显著。治疗组总有效率87.3%,血糖复常率53%,中医证候总有效率95.8%,从4周开始各项中医症状均改善并且持续至观测结束(24周)。用药后受试者生命体征平稳,治疗组有9例出现不良事件,不良事件发生率2.5%,无不良反应发生；对照组有3例出现不良事件,不良事件发生率2.5%,无不良反应发生。两组不良事件与不良反应比较差异无统计学意义(P>0.05)。结论：作为国内首个治疗IGT的纯中药制剂,糖耐康颗粒能有效降低IGT患者餐后血糖,并有降低糖化血红蛋白的趋势,能显著并快速改善IGT患者临床症状,降低IGT向糖尿病的转归率,安全无毒,几无不良反应,患者依从性良好。
实验研究部分,目的：观察糖耐康颗粒中的主要成分单味中药番石榴叶总黄酮对体外培养的胰岛β细胞株(HIT-T15)细胞模型胰岛素抵抗信号通路的干预机制。方法：取80只雄性SD大鼠的HIT-T15体外培养,分为正常组、高糖组、胰岛素刺激组、番石榴叶总黄酮含药血清高组、番石榴叶总黄酮含药血清中组、番石榴叶总黄酮含药血清低组、番石榴叶总黄酮高组、番石榴叶总黄酮中组、番石榴叶总黄酮低组。依次进行5项实验：①HIT-T15胰岛p细胞生长曲线测定,用于确定使用合适时间范围的HIT-T15胰岛β细胞进行实验；②不同浓度葡萄糖对HIT-T15胰岛β细胞增殖的影响,用以确定高糖模型所需的葡萄糖浓度；③不同浓度番石榴叶总黄酮对高糖环境下HIT-T15胰岛β细胞增殖的影响,用于确定番石榴叶总黄酮最佳有效刺激浓度,分别使用了含血清和不含血清的番石榴叶总黄酮,以排除血清内活性因子的影响；④胰岛素分泌分析,观察番石榴叶总黄酮能否改善高糖环境下HIT-T15胰岛β细胞的胰岛素分泌；⑤实时荧光定量RT-PCR,运用相对定量法,比较各HIT-T15胰岛β细胞自身组胰岛素受体mRNA表达的差异,用以确定番石榴叶总黄酮对HIT-T15胰岛β细胞可能的作用靶点。结果：番石榴叶总黄酮可以改善高糖刺激下的HIT-T15胰岛p细胞胰岛素分泌减低,改善胰岛p细胞胰自身胰岛素受体(?)nRNA的表达。结论：番石榴叶总黄酮能够改善高糖诱导的HIT-T15胰岛β细胞胰岛素抵抗,其作用机理可能与改善HIT-T15胰岛p细胞胰岛素受体基因表达有关。
This paper consists of literature review, experimental study and clinical research.
Literature review summarizes the intervention of traditional Chinese medicine research progress of abnormal glucose tolerance. Firstly summarizes the physicians embalmed in IGT (PiDan) the understanding of the etiology and pathogenesis, and then analysis of the current epidemiological studies some main understanding of IGT card type, then discusses the main method and progress of TCM intervention IGT in recent years, the last of IGT mechanism of traditional Chinese medicine research content.
Clinical section called TangNaiKang granules treatment in phase III clinical trials, impaired glucose tolerance, objective:further evaluation TangNaiKang granules treatment clinical curative effect and safety of IGT. Methods:multicenter, randomized, double-blind, placebo parallel control design, a total of480subjects according to the proportion of3:1randomly assigned into the treatment group (TangNaiKang granule group) and control group (placebo), a12-week intervention. Results:12wk, a drug treatment group, postprandial2hours blood glucose changes than the control group compared with statistical significance (P<0.05), treatment group was superior to control group. For12wk, a FBS, FINS,2hins compared with baseline, the two groups have no statistical difference, but there is a decrease in the treatment group than the control group in HbAlc data trend. Blood lipids observed indexes were no significant difference between two groups. Significant difference was found in TCM syndrome integral. Treatment group total effectiveness87.3%, after blood sugar often rate53%, TCM syndrome total effective rate95.8%, from the TCM symptoms were improved and lasts for4weeks until the end of observation (24weeks). Subjects stable vital signs, the medicine treatment group has9cases appear adverse events, adverse event rate by2.5%, and no adverse reactions occurred;Control group has3cases appear adverse events, adverse events incidence2.5%, no adverse reaction occurred. Adverse events and adverse reaction is similar between the two groups has no statistical significance (P>0.05). Conclusion:as the first domestic new agents for the treatment of IGT, TangNaiKang granule can effectively reduce the IGT patients with postprandial blood sugar, and has a tendency to lower glycosylated hemoglobin, significantly and quickly improve clinical symptoms in patients with IGT, decrease the rate of IGT to diabetes outcomes, safe non-toxic, few adverse effects, patient compliance is good.
Experimental research part, objective:to observe the main ingredient in sugar resistant kang granules of single taste traditional Chinese medicine (TCM) guava leaf flavonoids on in vitro cultured islet beta cell lines (HIT-T15) intervention mechanism of cellular model of insulin resistance signal pathway. Methods:80male SD rats HIT-T15in vitro culture, divided into normal group, high sugar, insulin stimulation group, guava leaf flavonoids drug-containing serum group, guava leaf flavonoids containing medicine serum group, guava leaf flavonoids containing medicine serum low group, guava leaf flavonoids is high, guava leaf flavonoids in groups, guava leaf flavonoids is low. In turn five experiments:(1) HIT-T15islet beta cells growth curve determination, used to determine the suitable time range of HIT-T15islet beta cells in the experiment;(2) different concentrations of glucose on HIT-T15islet beta cell proliferation, the influence of high sugar model is used to determine the concentration of glucose; Guava leaf flavonoids (3) different concentrations of high sugar HIT-the T15islet beta cell proliferation, used to determine the guava leaf flavonoids best effective stimulus concentration, respectively, using the contain and free serum guava leaf flavonoids, to eliminate the effects of the active factor in serum;(4) insulin secretion analysis, observation of guava leaf flavonoids can improve high sugar HIT-the T15islet beta cells insulin secretion;(5) real time fluorescence quantitative rt-pcr, using relative quantitative method, comparing the HIT-T15islet beta cells themselves group differences in insulin receptor mRNA expression, is used to determine the guava leaf flavonoids to HIT-T15islet beta cells possible targets. Results:guava leaf flavonoids can improve sugar under the stimulus of HIT-T15insulin secretion reduce islet beta cells, improve pancreatic islet beta cells themselves insulin receptor mRNA expression. Conclusion:guava leaf flavonoids can improve the HIT-T15islet beta cells induced by high sugar insulin resistance and its mechanism may be related to improve HIT-T15islet beta cells is related to insulin receptor gene expression.
文献综述总结了中医药干预糖耐量异常的研究进展。首先总结了古今医家对IGT(脾瘅)病因病机的认识,接着分析了目前一些主要流行病学研究对IGT证型的认识,其后讨论了近年来中医药干预IGT的主要方法和进展,最后涉及了一些中医药研究IGT机制的内容。
临床部分即糖耐康颗粒治疗糖耐量异常的Ⅲ期临床试验,目的：进一步评价糖耐康颗粒治疗IGT的临床疗效及安全性。方法：采用多中心、随机、双盲、安慰剂平行对照设计,共480例受试者按3：1比例随机分入治疗组(糖耐康颗粒组)和对照组(安慰剂组),进行为期12周的干预。结果：用药12wk,治疗组餐后2小时血糖变化较对照组比较有统计学意义(P<0.05),治疗组优于对照组。给药12wk, FBS、FINS、2hINS与基线相比,两组无统计学差异,但HbAlc数据中治疗组较对照组有下降趋势。血脂观测指标在两组间均无显著差异。中医证候积分差异显著。治疗组总有效率87.3%,血糖复常率53%,中医证候总有效率95.8%,从4周开始各项中医症状均改善并且持续至观测结束(24周)。用药后受试者生命体征平稳,治疗组有9例出现不良事件,不良事件发生率2.5%,无不良反应发生；对照组有3例出现不良事件,不良事件发生率2.5%,无不良反应发生。两组不良事件与不良反应比较差异无统计学意义(P>0.05)。结论：作为国内首个治疗IGT的纯中药制剂,糖耐康颗粒能有效降低IGT患者餐后血糖,并有降低糖化血红蛋白的趋势,能显著并快速改善IGT患者临床症状,降低IGT向糖尿病的转归率,安全无毒,几无不良反应,患者依从性良好。
实验研究部分,目的：观察糖耐康颗粒中的主要成分单味中药番石榴叶总黄酮对体外培养的胰岛β细胞株(HIT-T15)细胞模型胰岛素抵抗信号通路的干预机制。方法：取80只雄性SD大鼠的HIT-T15体外培养,分为正常组、高糖组、胰岛素刺激组、番石榴叶总黄酮含药血清高组、番石榴叶总黄酮含药血清中组、番石榴叶总黄酮含药血清低组、番石榴叶总黄酮高组、番石榴叶总黄酮中组、番石榴叶总黄酮低组。依次进行5项实验：①HIT-T15胰岛p细胞生长曲线测定,用于确定使用合适时间范围的HIT-T15胰岛β细胞进行实验；②不同浓度葡萄糖对HIT-T15胰岛β细胞增殖的影响,用以确定高糖模型所需的葡萄糖浓度；③不同浓度番石榴叶总黄酮对高糖环境下HIT-T15胰岛β细胞增殖的影响,用于确定番石榴叶总黄酮最佳有效刺激浓度,分别使用了含血清和不含血清的番石榴叶总黄酮,以排除血清内活性因子的影响；④胰岛素分泌分析,观察番石榴叶总黄酮能否改善高糖环境下HIT-T15胰岛β细胞的胰岛素分泌；⑤实时荧光定量RT-PCR,运用相对定量法,比较各HIT-T15胰岛β细胞自身组胰岛素受体mRNA表达的差异,用以确定番石榴叶总黄酮对HIT-T15胰岛β细胞可能的作用靶点。结果：番石榴叶总黄酮可以改善高糖刺激下的HIT-T15胰岛p细胞胰岛素分泌减低,改善胰岛p细胞胰自身胰岛素受体(?)nRNA的表达。结论：番石榴叶总黄酮能够改善高糖诱导的HIT-T15胰岛β细胞胰岛素抵抗,其作用机理可能与改善HIT-T15胰岛p细胞胰岛素受体基因表达有关。
This paper consists of literature review, experimental study and clinical research.
Literature review summarizes the intervention of traditional Chinese medicine research progress of abnormal glucose tolerance. Firstly summarizes the physicians embalmed in IGT (PiDan) the understanding of the etiology and pathogenesis, and then analysis of the current epidemiological studies some main understanding of IGT card type, then discusses the main method and progress of TCM intervention IGT in recent years, the last of IGT mechanism of traditional Chinese medicine research content.
Clinical section called TangNaiKang granules treatment in phase III clinical trials, impaired glucose tolerance, objective:further evaluation TangNaiKang granules treatment clinical curative effect and safety of IGT. Methods:multicenter, randomized, double-blind, placebo parallel control design, a total of480subjects according to the proportion of3:1randomly assigned into the treatment group (TangNaiKang granule group) and control group (placebo), a12-week intervention. Results:12wk, a drug treatment group, postprandial2hours blood glucose changes than the control group compared with statistical significance (P<0.05), treatment group was superior to control group. For12wk, a FBS, FINS,2hins compared with baseline, the two groups have no statistical difference, but there is a decrease in the treatment group than the control group in HbAlc data trend. Blood lipids observed indexes were no significant difference between two groups. Significant difference was found in TCM syndrome integral. Treatment group total effectiveness87.3%, after blood sugar often rate53%, TCM syndrome total effective rate95.8%, from the TCM symptoms were improved and lasts for4weeks until the end of observation (24weeks). Subjects stable vital signs, the medicine treatment group has9cases appear adverse events, adverse event rate by2.5%, and no adverse reactions occurred;Control group has3cases appear adverse events, adverse events incidence2.5%, no adverse reaction occurred. Adverse events and adverse reaction is similar between the two groups has no statistical significance (P>0.05). Conclusion:as the first domestic new agents for the treatment of IGT, TangNaiKang granule can effectively reduce the IGT patients with postprandial blood sugar, and has a tendency to lower glycosylated hemoglobin, significantly and quickly improve clinical symptoms in patients with IGT, decrease the rate of IGT to diabetes outcomes, safe non-toxic, few adverse effects, patient compliance is good.
Experimental research part, objective:to observe the main ingredient in sugar resistant kang granules of single taste traditional Chinese medicine (TCM) guava leaf flavonoids on in vitro cultured islet beta cell lines (HIT-T15) intervention mechanism of cellular model of insulin resistance signal pathway. Methods:80male SD rats HIT-T15in vitro culture, divided into normal group, high sugar, insulin stimulation group, guava leaf flavonoids drug-containing serum group, guava leaf flavonoids containing medicine serum group, guava leaf flavonoids containing medicine serum low group, guava leaf flavonoids is high, guava leaf flavonoids in groups, guava leaf flavonoids is low. In turn five experiments:(1) HIT-T15islet beta cells growth curve determination, used to determine the suitable time range of HIT-T15islet beta cells in the experiment;(2) different concentrations of glucose on HIT-T15islet beta cell proliferation, the influence of high sugar model is used to determine the concentration of glucose; Guava leaf flavonoids (3) different concentrations of high sugar HIT-the T15islet beta cell proliferation, used to determine the guava leaf flavonoids best effective stimulus concentration, respectively, using the contain and free serum guava leaf flavonoids, to eliminate the effects of the active factor in serum;(4) insulin secretion analysis, observation of guava leaf flavonoids can improve high sugar HIT-the T15islet beta cells insulin secretion;(5) real time fluorescence quantitative rt-pcr, using relative quantitative method, comparing the HIT-T15islet beta cells themselves group differences in insulin receptor mRNA expression, is used to determine the guava leaf flavonoids to HIT-T15islet beta cells possible targets. Results:guava leaf flavonoids can improve sugar under the stimulus of HIT-T15insulin secretion reduce islet beta cells, improve pancreatic islet beta cells themselves insulin receptor mRNA expression. Conclusion:guava leaf flavonoids can improve the HIT-T15islet beta cells induced by high sugar insulin resistance and its mechanism may be related to improve HIT-T15islet beta cells is related to insulin receptor gene expression.
引文
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