基于代谢组学的生脉注射液干预2型糖尿病气阴两虚证的临床研究
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摘要
目的：
通过对2型糖尿病气阴两虚证患者治疗前后血清进行代谢组学检测,观察生脉注射液干预前后代谢产物的变化及与对照组、健康组代谢产物的差别,比较其内源性物质的区别,根据这些内源性物质的变化规律,确定2型糖尿病气阴两虚证特异的代谢标记物,研究特征性代谢产物及其代谢途径在2型糖尿病气阴两虚证中所起的可能作用,为深入认识2型糖尿病的中医证候及其诊断提供研究基础,并探讨生脉注射液作用机制,为寻找治疗2型糖尿病的有效中药提供临床依据。
方法：
将纳入研究的2型糖尿病气阴两虚证患者48例随机分为治疗组28例、对照组20例,对照组采用胰岛素强化治疗,治疗组在对照组的基础上加用生脉注射液,采用气相色谱-质谱联用方法(gas chromatography-mass spectrometry, GC/MS)进行治疗前后代谢组学检测,应用主成分分析法(principal components analysis, PCA)和偏最小二乘判别分析法(partial least squares-discrimination analysis, PLS-DA)进行分析,采用PASW Statistics18.0软件,观察治疗前后、治疗组与对照组代谢产物的变化,同时与健康对照组40例进行代谢组学的对比,确定2型糖尿病气阴两虚证特异的代谢标记物及变化,并观察生脉注射液治疗2型糖尿病气阴两虚证微观作用机制。
结果：
1.治疗前一般检测项目：治疗组、对照组在性别、年龄、身高、体重、体重指数、腹围、腰围、腰臂比、病程、及证候表现方面如咽干口燥,倦怠乏力,多食易饥,口渴喜饮,五心烦热,汗出,心悸、小便短赤、大便干结及证候积分方面比较,P>0.05,差异无统计学意义；在常规生化检测方面如空腹血糖、餐后2h血糖、胆固酮、甘油三脂、高密度脂蛋白、低密度脂蛋白、糖化血红蛋白、空腹胰岛素、空腹C肽、白介素-6、肿瘤坏死因子等方面比较,P>0.05,差异无统计学意义；并计算胰岛素抵抗指数、胰岛素敏感指数、胰岛β细胞功能指数经统计P>0.05,差异无统计学意义。
2.治疗后临床生化指标比较：治疗后两组在空腹血糖、餐后2h血糖、胆固酮、甘油三脂、高密度脂蛋白、低密度脂蛋白、糖化血红蛋白、空腹胰岛素、空腹C肽等指标方面经统计分析,P<0.05，差异有统计学意义。
3.治疗后在胰岛抵抗指数、敏感指数比较：治疗后治疗组与对照组胰岛素抵抗指数、胰岛素敏感指数、胰岛β细胞功能比较,P<0.05,差异有统计学意义。治疗后两组在炎症因子白介素-6,肿瘤坏死因子方面比较,P 4.治疗后证候表现及积分比较：治疗后治疗组与对照组在证候表现方面比较,生脉注射液治疗组在口渴、证候总积分与对照组比较,P<0.05,差异有统计学意义；而对倦怠乏力、多食易饥、心悸、失眠、五心烦热、汗出等症状改善不明显,P>0.05,差异无统计学意义。
5.2型糖尿病气阴两虚证潜在生物标记物：2型糖尿病气阴两虚证潜在生物标记物主要有磷脂酰甘油、甘油三脂、卵磷脂、棕榈酰葡萄糖醛酸、三甲基乙酰、L-脯氨酸、缓激肽羟脯氨酸、苯丙氨酰-谷氨酰胺、苯丙氨酰-天冬酰胺、假尿嘧啶核苷5’-磷酸,并且经生物标志物含量测定及健康组比较,P<0.05,差异有统计学意义。
6.治疗组潜在生物标志物鉴定：治疗组治疗前、后血浆代谢产物鉴定,并与健康组比较,其潜在生物标志物主要有甘油三酯、11’-羧基-α-苯并二氢吡喃醇、磷脂酰丝氨酸、磷脂酰甘油、棕榈酰葡萄糖醛酸、甘油磷酸胆碱、牛磺酸脱氧胆酸、脲基琥珀酸、蛋氨酸、溶血性磷脂酰胆碱、1,4-β-D-葡聚糖、β-D-葡萄糖,并经生物标志物含量测定及对比,P<0.05,差异有统计学意义。
7.对照组潜在生物标志物鉴定：对照组治疗前、后血浆代谢产物鉴定,并与健康组比较,其潜在生物标志物主要有溶血磷脂酸、磷脂酰乙醇胺、神经节苷脂、卵磷脂、甘油二酯、心磷脂、甘油三酯、溶血磷脂、磷脂酰肌醇磷酸、胆甾烯基癸酸酯、二氢生物蝶呤、脲基琥珀酸,并且经生物标志物含量测定及对比,P<0.05,差异有统计学意义。
8.两组治疗后潜在生物标志物鉴定：治疗组与对照组治疗后生物标志物鉴定,并与健康组比较,其潜在生物标志物主要有磷脂酰乙醇胺、神经节苷脂、甘油三脂、二磷酸磷脂酰肌醇、溶血磷脂、甘油二酯、磷脂酰胆碱、尿囊酸、苯丙氨酰-天冬酰胺、异亮氨酰-苯丙氨酸,并且经生物标志物含量测定及对比,P<0.05,差异有统计学意义。
结论：
1.2型糖尿病气阴两虚证有特异的代谢标记物,与健康对照组比较存在内源性代谢产物差异。
2.2型糖尿病气阴两虚证治疗前后与健康对照组之间存在代谢产物的差异,且生脉注射液治疗组优于对照组。
3.生脉注射液能改善2型糖尿病气阴两虚证患者空腹血糖、餐后2h血糖、血脂、糖化血红蛋白、空腹胰岛素、空腹C肽及血管炎症因子如白介素-6,肿瘤坏死因子等指标,且能改善2型糖尿病气阴两虚证患者胰岛素抵抗指数、敏感指数及胰岛β细胞功能,疗效优于对照组。
4.生脉注射液能改善2型糖尿病气阴两虚证患者口渴证候表现及证候总积分,疗效优于对照组。
Objective
Study on type2diabetes patients with Qi and Yin deficiency syndrome before and after treatment serum detection of metabonomics, Observation of Shengmai injection intervention before and after the change of metabolites with the control group, the healthy group metabolite differences, compare the difference between the endogenous substances, according to these changes of endogenous substances, determine the metabolic markers of Qi and yin deficiency syndrome of type2diabetes mellitus, determined with type2diabetes Qi and Yin Deficiency specific metabolic markers characteristic of metabolites and metabolic pathways, and provides research foundation for in-depth understanding of type2diabetes and its diagnosis of TCM syndromes, at the same time explore Shengmai injection mechanism for finding an effective treatment of type2diabetes medicine provide clinical basis.
Methods
Will be incorporated into the study of type2diabetes Qi and Yin Deficiency48patients were randomly divided into treatment group of28patients and the control group of20patients. Control group with intensive insulin therapy, The treatment group was treated with Shengmai Injection on the basis of control group, by gas chromatography-mass spectrometry method (gas chromatography-mass spectrometry, GC/MS) before and after treatment metabolomics detection, principal component analysis (principal components analysis, PCA) and partial least squares discriminant analysis (partial least squares-discrimination analysis, PLS-DA) were analyzed using PASW Statisticsl8.0software, Observation the changes in metabolites before and after treatment, the treatment group and control group, at the same time with the healthy control group40cases of metabonomics in the comparison and to identify type2diabetes Qi Deficiency and specific changes in metabolic markers and observe Shengmai injection treatment of type2diabetes Qi Deficiency microscopic mechanism.
Results
1.Before treatment, the general test items:the treatment group and the control group in terms of gender, age, height, weight, body mass index, waist circumference, waist circumference, WHR, duration, and syndromes such as dry mouth and throat performance, fatigue, and more food easy to hunger, thirst hi drink, five upset hot, sweating, heart palpitations, scanty dark urine, dry stool and symptom integral, P>0.05, the difference was not statistically significant; In terms of routine biochemical tests such as fasting blood glucose, meal2h after glucose, ketones cholesterol, triglycerides, HDL, LDL, glycated hemoglobin, fasting insulin, fasting C-peptide, interleukin-6, tumor necrosis factor, etc., P>0.05, the difference was not statistically significance;and insulin resistance index, insulin sensitivity index and islet3cell function index by statistical P>0.05, the difference was not statistically significant.
2. After treatment, clinical biochemical comparison:After treatment, the fasting blood glucose, postprandial2h plasma glucose, ketones cholesterol, triglycerides, HDL, LDL, glycated hemoglobin, fasting insulin, fasting C-peptide and other indicators after statistical analysis, P<0.05, the difference was statistically significant.
3. After treatment in insulin resistance index, sensitive index comparison: the treatment group and the control group index of insulin resistance, insulin sensitivity index, islet β-cell function compared, P<0.05, the difference was statistically significant. After treatment, the inflammatory cytokines interleukin-6, tumor necrosis factor with relatively, P<0.05, the difference was statistically significant.
4. Syndrome after treatment performance and integral comparison:The treatment group and the control group in comparison syndromes performance Shengmai injection treatment group in thirst, syndromes total score compared with control group, P<0.05, the di fference was stati stically significant;while fatigue, and more food easy to hunger, palpitations, insomnia, five upset hot, sweating and other symptoms were not obvious, by comparison, P>0.05, the difference was not statistically significant.
5. Type2Diabetes Qi and Yin Deficiency potential biomarkers:Type2 diabetes Qi and Yin Deficiency potential biomarkers are phosphatidyl glycerol, triglycerides, lecithin, palmitic acid, glucuronic acid, trimethyl acetyl, L-proline, hydroxyproline bradykinin, phenylalanyl-glutamine, phenylalanyl-asparagine, false uridine5'-phosphate, and by the determination of biomarkers and health group, P<0.05, the difference was statistically significant.
6. The treatment group identified potential biomarkers:the treatment group before and after treatment of plasma metabolites identified and compared with the healthy group, its potential biomarkers are mainly triglycerides,11'-carboxy-α-benzo dihydropyrazole furans alcohol, phosphatidyl serine, phosphatidyl glycerol, palmitoyl-glucuronic acid, glycerol phosphate, choline, taurine, deoxycholic acid, ureido acid, methionine, hemolytic phosphatidylcholine,1,4-β-D-glucan, β-D-glucose, and by the determination of biomarkers and contrast, P<0.05, the difference was statistically significant.
7.The control group identified potential biomarkers:the control group before and after treatment of plasma metabolites identified and compared with the healthy group, its potential biomarkers are lysophosphatidic acid, phosphatidyl ethanolamine, gangliosides, lecithin, diglyceride, cardiolipin, triglycerides, lysophospholipids, phosphatidyl inositol phosphate, decyl cholesteryl ester, dihydro-biopterin, ureido acid, and by the determination of biomarkers and contrast, P<0.05, the difference was statistically significant.
8. The two groups after treatment of potential biomarker identification: the treatment group and the control group after treatment, biomarker identification, and compared with the healthy group, its potential biomarkers mainly phosphatidylethanolamine, ganglioside, triglycerides, phosphatidylinositol diphosphate, lysophospholipids, diglycerides, phosphatidyl choline, allantoic acid, phenylalanyl-asparagine, isoleucyl-phenylalanine, and by determination of biomarkers and contrast,P<0.05, the difference was statistically significant.
Conclusions
1.Type2Diabetes Qi and Yin Deficiency has a specific metabolic markers, compared with the healthy control group, the presence of endogenous metabolites difference.
2. Type2Diabetes Qi and Yin Deficiency before and after treatment with the healthy control group differences exist between metabolites and Shengmai Injection in the treatment group superior to the control group.
3. Shengmai injection can improve type2diabetes patients with Qi and Yin Deficiency in fasting glucose,2h postprandial blood glucose, blood lipids, glycated hemoglobin, fasting insulin, fasting C-peptide and vascular inflammatory cytokines such as interleukin-6, tumor necrosis factor and other indicators, and can improve the Qi and Yin Deficiency patients with type2diabetes insulin resistance index, sensitivity index and pancreatic β-cell function, more effective than the control group.
4. Shengmai injection can improve type2diabetes patients with Qi and Yin Deficiency Syndrome thirst performance and syndrome total score, the more effective superior to the control group.
通过对2型糖尿病气阴两虚证患者治疗前后血清进行代谢组学检测,观察生脉注射液干预前后代谢产物的变化及与对照组、健康组代谢产物的差别,比较其内源性物质的区别,根据这些内源性物质的变化规律,确定2型糖尿病气阴两虚证特异的代谢标记物,研究特征性代谢产物及其代谢途径在2型糖尿病气阴两虚证中所起的可能作用,为深入认识2型糖尿病的中医证候及其诊断提供研究基础,并探讨生脉注射液作用机制,为寻找治疗2型糖尿病的有效中药提供临床依据。
方法：
将纳入研究的2型糖尿病气阴两虚证患者48例随机分为治疗组28例、对照组20例,对照组采用胰岛素强化治疗,治疗组在对照组的基础上加用生脉注射液,采用气相色谱-质谱联用方法(gas chromatography-mass spectrometry, GC/MS)进行治疗前后代谢组学检测,应用主成分分析法(principal components analysis, PCA)和偏最小二乘判别分析法(partial least squares-discrimination analysis, PLS-DA)进行分析,采用PASW Statistics18.0软件,观察治疗前后、治疗组与对照组代谢产物的变化,同时与健康对照组40例进行代谢组学的对比,确定2型糖尿病气阴两虚证特异的代谢标记物及变化,并观察生脉注射液治疗2型糖尿病气阴两虚证微观作用机制。
结果：
1.治疗前一般检测项目：治疗组、对照组在性别、年龄、身高、体重、体重指数、腹围、腰围、腰臂比、病程、及证候表现方面如咽干口燥,倦怠乏力,多食易饥,口渴喜饮,五心烦热,汗出,心悸、小便短赤、大便干结及证候积分方面比较,P>0.05,差异无统计学意义；在常规生化检测方面如空腹血糖、餐后2h血糖、胆固酮、甘油三脂、高密度脂蛋白、低密度脂蛋白、糖化血红蛋白、空腹胰岛素、空腹C肽、白介素-6、肿瘤坏死因子等方面比较,P>0.05,差异无统计学意义；并计算胰岛素抵抗指数、胰岛素敏感指数、胰岛β细胞功能指数经统计P>0.05,差异无统计学意义。
2.治疗后临床生化指标比较：治疗后两组在空腹血糖、餐后2h血糖、胆固酮、甘油三脂、高密度脂蛋白、低密度脂蛋白、糖化血红蛋白、空腹胰岛素、空腹C肽等指标方面经统计分析,P<0.05，差异有统计学意义。
3.治疗后在胰岛抵抗指数、敏感指数比较：治疗后治疗组与对照组胰岛素抵抗指数、胰岛素敏感指数、胰岛β细胞功能比较,P<0.05,差异有统计学意义。治疗后两组在炎症因子白介素-6,肿瘤坏死因子方面比较,P
5.2型糖尿病气阴两虚证潜在生物标记物：2型糖尿病气阴两虚证潜在生物标记物主要有磷脂酰甘油、甘油三脂、卵磷脂、棕榈酰葡萄糖醛酸、三甲基乙酰、L-脯氨酸、缓激肽羟脯氨酸、苯丙氨酰-谷氨酰胺、苯丙氨酰-天冬酰胺、假尿嘧啶核苷5’-磷酸,并且经生物标志物含量测定及健康组比较,P<0.05,差异有统计学意义。
6.治疗组潜在生物标志物鉴定：治疗组治疗前、后血浆代谢产物鉴定,并与健康组比较,其潜在生物标志物主要有甘油三酯、11’-羧基-α-苯并二氢吡喃醇、磷脂酰丝氨酸、磷脂酰甘油、棕榈酰葡萄糖醛酸、甘油磷酸胆碱、牛磺酸脱氧胆酸、脲基琥珀酸、蛋氨酸、溶血性磷脂酰胆碱、1,4-β-D-葡聚糖、β-D-葡萄糖,并经生物标志物含量测定及对比,P<0.05,差异有统计学意义。
7.对照组潜在生物标志物鉴定：对照组治疗前、后血浆代谢产物鉴定,并与健康组比较,其潜在生物标志物主要有溶血磷脂酸、磷脂酰乙醇胺、神经节苷脂、卵磷脂、甘油二酯、心磷脂、甘油三酯、溶血磷脂、磷脂酰肌醇磷酸、胆甾烯基癸酸酯、二氢生物蝶呤、脲基琥珀酸,并且经生物标志物含量测定及对比,P<0.05,差异有统计学意义。
8.两组治疗后潜在生物标志物鉴定：治疗组与对照组治疗后生物标志物鉴定,并与健康组比较,其潜在生物标志物主要有磷脂酰乙醇胺、神经节苷脂、甘油三脂、二磷酸磷脂酰肌醇、溶血磷脂、甘油二酯、磷脂酰胆碱、尿囊酸、苯丙氨酰-天冬酰胺、异亮氨酰-苯丙氨酸,并且经生物标志物含量测定及对比,P<0.05,差异有统计学意义。
结论：
1.2型糖尿病气阴两虚证有特异的代谢标记物,与健康对照组比较存在内源性代谢产物差异。
2.2型糖尿病气阴两虚证治疗前后与健康对照组之间存在代谢产物的差异,且生脉注射液治疗组优于对照组。
3.生脉注射液能改善2型糖尿病气阴两虚证患者空腹血糖、餐后2h血糖、血脂、糖化血红蛋白、空腹胰岛素、空腹C肽及血管炎症因子如白介素-6,肿瘤坏死因子等指标,且能改善2型糖尿病气阴两虚证患者胰岛素抵抗指数、敏感指数及胰岛β细胞功能,疗效优于对照组。
4.生脉注射液能改善2型糖尿病气阴两虚证患者口渴证候表现及证候总积分,疗效优于对照组。
Objective
Study on type2diabetes patients with Qi and Yin deficiency syndrome before and after treatment serum detection of metabonomics, Observation of Shengmai injection intervention before and after the change of metabolites with the control group, the healthy group metabolite differences, compare the difference between the endogenous substances, according to these changes of endogenous substances, determine the metabolic markers of Qi and yin deficiency syndrome of type2diabetes mellitus, determined with type2diabetes Qi and Yin Deficiency specific metabolic markers characteristic of metabolites and metabolic pathways, and provides research foundation for in-depth understanding of type2diabetes and its diagnosis of TCM syndromes, at the same time explore Shengmai injection mechanism for finding an effective treatment of type2diabetes medicine provide clinical basis.
Methods
Will be incorporated into the study of type2diabetes Qi and Yin Deficiency48patients were randomly divided into treatment group of28patients and the control group of20patients. Control group with intensive insulin therapy, The treatment group was treated with Shengmai Injection on the basis of control group, by gas chromatography-mass spectrometry method (gas chromatography-mass spectrometry, GC/MS) before and after treatment metabolomics detection, principal component analysis (principal components analysis, PCA) and partial least squares discriminant analysis (partial least squares-discrimination analysis, PLS-DA) were analyzed using PASW Statisticsl8.0software, Observation the changes in metabolites before and after treatment, the treatment group and control group, at the same time with the healthy control group40cases of metabonomics in the comparison and to identify type2diabetes Qi Deficiency and specific changes in metabolic markers and observe Shengmai injection treatment of type2diabetes Qi Deficiency microscopic mechanism.
Results
1.Before treatment, the general test items:the treatment group and the control group in terms of gender, age, height, weight, body mass index, waist circumference, waist circumference, WHR, duration, and syndromes such as dry mouth and throat performance, fatigue, and more food easy to hunger, thirst hi drink, five upset hot, sweating, heart palpitations, scanty dark urine, dry stool and symptom integral, P>0.05, the difference was not statistically significant; In terms of routine biochemical tests such as fasting blood glucose, meal2h after glucose, ketones cholesterol, triglycerides, HDL, LDL, glycated hemoglobin, fasting insulin, fasting C-peptide, interleukin-6, tumor necrosis factor, etc., P>0.05, the difference was not statistically significance;and insulin resistance index, insulin sensitivity index and islet3cell function index by statistical P>0.05, the difference was not statistically significant.
2. After treatment, clinical biochemical comparison:After treatment, the fasting blood glucose, postprandial2h plasma glucose, ketones cholesterol, triglycerides, HDL, LDL, glycated hemoglobin, fasting insulin, fasting C-peptide and other indicators after statistical analysis, P<0.05, the difference was statistically significant.
3. After treatment in insulin resistance index, sensitive index comparison: the treatment group and the control group index of insulin resistance, insulin sensitivity index, islet β-cell function compared, P<0.05, the difference was statistically significant. After treatment, the inflammatory cytokines interleukin-6, tumor necrosis factor with relatively, P<0.05, the difference was statistically significant.
4. Syndrome after treatment performance and integral comparison:The treatment group and the control group in comparison syndromes performance Shengmai injection treatment group in thirst, syndromes total score compared with control group, P<0.05, the di fference was stati stically significant;while fatigue, and more food easy to hunger, palpitations, insomnia, five upset hot, sweating and other symptoms were not obvious, by comparison, P>0.05, the difference was not statistically significant.
5. Type2Diabetes Qi and Yin Deficiency potential biomarkers:Type2 diabetes Qi and Yin Deficiency potential biomarkers are phosphatidyl glycerol, triglycerides, lecithin, palmitic acid, glucuronic acid, trimethyl acetyl, L-proline, hydroxyproline bradykinin, phenylalanyl-glutamine, phenylalanyl-asparagine, false uridine5'-phosphate, and by the determination of biomarkers and health group, P<0.05, the difference was statistically significant.
6. The treatment group identified potential biomarkers:the treatment group before and after treatment of plasma metabolites identified and compared with the healthy group, its potential biomarkers are mainly triglycerides,11'-carboxy-α-benzo dihydropyrazole furans alcohol, phosphatidyl serine, phosphatidyl glycerol, palmitoyl-glucuronic acid, glycerol phosphate, choline, taurine, deoxycholic acid, ureido acid, methionine, hemolytic phosphatidylcholine,1,4-β-D-glucan, β-D-glucose, and by the determination of biomarkers and contrast, P<0.05, the difference was statistically significant.
7.The control group identified potential biomarkers:the control group before and after treatment of plasma metabolites identified and compared with the healthy group, its potential biomarkers are lysophosphatidic acid, phosphatidyl ethanolamine, gangliosides, lecithin, diglyceride, cardiolipin, triglycerides, lysophospholipids, phosphatidyl inositol phosphate, decyl cholesteryl ester, dihydro-biopterin, ureido acid, and by the determination of biomarkers and contrast, P<0.05, the difference was statistically significant.
8. The two groups after treatment of potential biomarker identification: the treatment group and the control group after treatment, biomarker identification, and compared with the healthy group, its potential biomarkers mainly phosphatidylethanolamine, ganglioside, triglycerides, phosphatidylinositol diphosphate, lysophospholipids, diglycerides, phosphatidyl choline, allantoic acid, phenylalanyl-asparagine, isoleucyl-phenylalanine, and by determination of biomarkers and contrast,P<0.05, the difference was statistically significant.
Conclusions
1.Type2Diabetes Qi and Yin Deficiency has a specific metabolic markers, compared with the healthy control group, the presence of endogenous metabolites difference.
2. Type2Diabetes Qi and Yin Deficiency before and after treatment with the healthy control group differences exist between metabolites and Shengmai Injection in the treatment group superior to the control group.
3. Shengmai injection can improve type2diabetes patients with Qi and Yin Deficiency in fasting glucose,2h postprandial blood glucose, blood lipids, glycated hemoglobin, fasting insulin, fasting C-peptide and vascular inflammatory cytokines such as interleukin-6, tumor necrosis factor and other indicators, and can improve the Qi and Yin Deficiency patients with type2diabetes insulin resistance index, sensitivity index and pancreatic β-cell function, more effective than the control group.
4. Shengmai injection can improve type2diabetes patients with Qi and Yin Deficiency Syndrome thirst performance and syndrome total score, the more effective superior to the control group.
引文
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