2型糖尿病火热病机与代谢指标相关性和清热益气中药作用机制研究
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摘要
研究背景
糖尿病(diabetes mellitus, DM)的发病率在世界各国日益飙升,2型糖尿病(type2diabetes mellitus, T2DM)是DM最常见的类型,严重威胁着人类的健康。T2DM属于中医学“消渴病”范畴,中医学对其病因病机的认识由来已久,早在《内经》中就有“壮火食气”,“二阳结,谓之消”的论述。随着现代生活方式的改变,疾病谱随之变化,传统的T2DM“阴虚燥热”病机认识指导益气养阴法治疗T2DM常不能取得满意疗效,提示我们需要重新认识T2DM证候分布与病因病机。
研究目的
通过证候学调查,研究T2DM患者的证候分布特点,及其变化与理化指标之间的相关性,重点关注火热证候的可能出现形式及分布情况,以期揭示火热证候在T2DM中的分布情况与导致其发生变化的相关因素,探索《内经》“壮火食气”理论,在T2DM病机假说中的科学性,丰富T2DM病机理论。
通过实验研究,探索清热益气药物黄连人参改善胰岛功能,促进p细胞损伤修复的作用机制,以期揭示清热益气治疗理论对β细胞保护的作用机理,从而验证“壮火食气”病机理论,丰富其科学内涵,为中医药治疗2型糖尿病提供新思路。
研究方法
1临床研究
通过横断面调查,观察T2DM患者一般情况,症状、代谢指标、胰岛功能等客观指标。对症状、证候要素进行频数统计、聚类及因子分析,比较不同证候要素患者的客观指标差异,并进行典型相关分析。通过7天纵向观察,比较两次证候调查结果与日间血糖波动的变化,对证候要素变化与血糖波动之间的相关性进行多元线性回归分析。
2实验研究
通过高热量高脂饲料喂养诱导GK大鼠,建立自发性T2DM大鼠模型,采用清热益气中药黄连人参对药进行干预,并设Wistar大鼠进行对照,观察黄连人参对代谢的调节作用,炎症因子水平及脂联素水平,进行胰腺病理学检测,观察其对胰岛结构的损伤修复作用,及TNF-α、脂联素受体、细胞凋亡因子在胰岛内表达。
研究结果
1临床研究
T2DM患者中,男性的发病高峰较女性早10岁左右,并且男性患者的年轻化趋势较女性更为严重,肥胖或超重在T2DM患者中普遍存在,与性别无关。T2DM早期并发症以DR、DPN、DN发生率较高,合并症中以高脂血症、高血压病、脂肪肝、冠心病出现率最高。
T2DM证候基本特点为：证候以虚实夹杂为主,单纯实证或单纯虚证相对少见；本虚证以气虚证、阴虚证为主,阳虚证相对较少,血虚证则未出现；标实证中,内热证普遍存在,痰湿证、血瘀证也较为突出,也有气郁证出现。内热证的表现形式多种多样,既可与痰湿、气郁、血瘀相兼为患,表现为湿热、郁热、瘀热,也可单独出现。其核心病位在肝胆、脾胃、胃肠,也可累及心与肺、肾。
HbAlc、LDL-C水平均与内热证相关,UAE水平与气虚证、痰湿证相关,TG水平既与内热证程度相关,又与痰湿证相关,UA、TC、HDL-C水平与痰湿证相关,BUN水平与阴虚证、阳虚证相关。内热证、痰湿证、血瘀证与胰岛功能关系密切,其中血糖水平及胰岛β细胞需求程度与内热证相关,胰岛p细胞功能、胰岛处置能力及胰岛素、C-肽水平与血瘀证、内热证均相关,胰岛素、C-肽水平、BMI及胰岛素抵抗水平、胰岛素敏感性痰湿证相关。
日间血糖波动也与证候变化相关,阴虚证积分变化与晚餐前血糖变化相关,阳虚证积分变化与晚餐后2小时血糖变化相关,气郁证积分变化与午餐前的血糖相关,而内热证积分变化则与三餐前后血糖变化均相关。
2实验研究
采用黄连人参治疗自发性T2DM大鼠模型4周,结果三组的体重、空腹胰岛素水平脂联素水平、胰岛素抵抗程度与胰岛素敏感性均无明显差异。模型组与黄连人参组餐后血糖、血脂、尿酸及血清超敏C反应蛋白水平均显著高于正常组,胰岛β细胞功能显著低于正常组,但两组间无明显差异。治疗后,黄连人参组的血清TNF-α水平及TNF-α、Bax在胰岛内表达均显著低于模型组与正常组无差异,而脂联素受体1的表达水平显著高于模型组,与正常组无差异,其胰岛结构紊乱程度也不及模型组严重。
研究结论
1临床研究
火热病机贯穿T2DM发生发展始终,是内热证候普遍存在的根本原因。
T2DM火热病机的实质是血糖、血脂代谢紊乱及胰岛功能损伤,内热既可与痰湿相合,又可与血瘀并见,均是导致T2DM发生发展的重要因素。
2实验研究
清热益气中药黄连人参的作用机制为下调促炎症因子及促凋亡因子在胰岛中的表达,上调脂联素受体在胰岛中的表达,从而促进胰岛β细胞的损伤修复。
Background
The incidence of diabetes (DM) is growing rapidly around the world. Type2diabetes (T2DM), which is the most common type of DM, is seriously threating human health. Traditional Chinese Medicine (TCM) has a great wealth of experience in treat with T2DM. As the dramatically change of modern lifestyle, the disease changes as well. The therapy of replenishing qi and nourishing yin, which guided by the traditional thinking often cannot achieve a satisfactory effect. Therefore, the TCM syndromes distribution, etiology and pathogenesis of T2DM need to be refreshed.
Objective
In order to be acquainted with the distribution of syndrome manifestations features of T2DM. and the correlation between the change of syndrome manifestations and objective indicators, especially the heat syndrome. So as to discover the mechanisms of heat-clearing and qi-replenishing drug. Coptis and ginseng in treating with T2DM and its action on beta-cell protection. Thus, verify the T2DM pathogenesis hypothesis "superheat consuming qi" to enrich T2DM pathogenesis theory, and provide new ideas for Chinese medicine treatment of type2diabetes.
Method
1Clinical research
Through the cross-sectional survey, we observed T2DM patients with general situation. symptoms, and objective indicators such as metabolic indicators, islet function. Analysis the symptoms and syndrome elements through frequeney cluster and factor analysis. Compare the differences of objective indicators among patients of different syndromes elements and do canonical correlation analysis as well. Through seven days longitudinal observation, compare the results of twice syndromes and blood glucose fluctuations, analysis the correlation between syndrome factors diversification and blood glucose fluctuations by multiple linear regression analysis.
2Experimental study
Set up the spontaneous T2DM rat model by GK rats induced by High-calorie high fat diet. using heat-clearing and qi-replenishing Chinese medicine Coptis and ginseng for intervention. and set Wistar rats as the control group, detecting the metabolic markers, inflammatory factors and adiponectin levels, as well as pancreatic pathology. So as to observe the islet structure damage repair effect of Coptis and ginseng, and TNF-alpha. adiponectin receptors apoptosis factor expression in islets.
Results
1Clinical research
The peak incidence of T2DM, men are about10years earlier than women.incidence of younger age in men are more serious than that in women. Over half of the T2DM patients are obese or overweight, regardless of gender. DR, DPN, DN are of the highest incidence of early T2DM complications. Hyperlipidemia, hypertension, fatty liver, and coronary heart disease are of the highest incidence of T2DM comorbidities.
The basic characteristics of T2DM syndromes are as follows:Syndromes mainly are deficiency-excess complications. Simple excess or simply deficiency syndromes are relatively rare; The main types of deficiency syndromes are qi and yin deficiency syndrome, and yang deficiency is relatively rare, while, blood deficiency syndrome does not appear in the survey. Meanwhile, for the excess syndromes, the internal heat syndromes are widespread, and the phlegm and blood stasis syndromes are also prominent, qi depression syndromes are exist as well. There are a variety of forms of the performance of the internal heat syndromes, which can appear with phlegm, qi depression or blood stasis simultaneously, and manifested as humid-heat, heat retention, stagnated heat, etc.,or appear alone as well. Its main loci are the liver and gallbladder, spleen and stomach, gastrointestinal, or involved with the heart, lung and kidney.
HbAlc, LDL-C levels are associated with the internal heat syndrome. UAE levels are associated with qi deficiency and phlegm syndrome. TG levels are associated with the degree of the internal heat syndrome as well as phlegm syndrome. UA.TC and HDI.-C levels are associated with phlegm. BUN levels are associated with yin and yang deficiency. There is close correlation among the internal heat, phlegm and blood stasis syndrome with islet function. Blood glucose levels and the extent of islet beta cells demand are related to the internal heat syndrome. The beta cell function, the deposition ability are both related to the blood stasis and the internal heat syndromes. BMI, insulin resistance level and insulin sensitivity are related to the phlegm syndrome.
The blood glucose fluctuations are also related with the change of syndromes. Yin deficiency syndrome change with the blood glucose levels of before dinner. Yang deficiency syndrome change with the blood glucose levels of2hours after dinner. Qi depression syndromes change with the blood glucose levels of before lunch. The internal heat syndrome change with the blood glucose levels of before and after every meal.
2Experimental study
Treat the spontaneous type2diabetic rats model with Coptis and ginseng treatment for4weeks, body weight, fasting insulin, adiponectin levels, insulin resistance and insulin sensitivity of the three groups had not significant difference.
The postprandial blood glucose, blood lipids, uric acid, and serum high sensitivity C reactive protein levels of the model group and the Coptis and ginseng group were significantly higher than for normal group, for islet beta cell function was significantly lower than normal group, but there is no significant difference between the two groups.
The serum TNF-alpha levels, islets TNF-alpha and Bax expression of Coptis and ginseng group were significantly lower than the model group, and had no difference with the normal group, and the expression of adiponectin receptor1in islet was significantly higher than that in the model group, and had no difference with the normal group.the degree of structural disorder of Islet is not that serious as the model group.
Conclusion
1Clinical research
It is the root of the reason that the heat pathogenesis goes throughout the whole course of T2DM. leading that the internal heat syndrome ubiquitous. The essence of T2DM heat pathogenesis is glucose metabolic disorder and which result in β-cell disfunction and apoptosis. The internal heat syndrome can conbine with either phlegm or blood stasis, which are both the important factors of T2DM progressing.
2Experimental study
The mechanism of Heat-clearing and qi-replenishing Chinese medicine Coptis and ginseng is that, down regulate the expression of proinflammatory cytokines and pro-apoptotic factors in islets, meanwhile increase the expression of adiponectin receptor in islets, thereby contributing to the islet beta-cell damage repair.
糖尿病(diabetes mellitus, DM)的发病率在世界各国日益飙升,2型糖尿病(type2diabetes mellitus, T2DM)是DM最常见的类型,严重威胁着人类的健康。T2DM属于中医学“消渴病”范畴,中医学对其病因病机的认识由来已久,早在《内经》中就有“壮火食气”,“二阳结,谓之消”的论述。随着现代生活方式的改变,疾病谱随之变化,传统的T2DM“阴虚燥热”病机认识指导益气养阴法治疗T2DM常不能取得满意疗效,提示我们需要重新认识T2DM证候分布与病因病机。
研究目的
通过证候学调查,研究T2DM患者的证候分布特点,及其变化与理化指标之间的相关性,重点关注火热证候的可能出现形式及分布情况,以期揭示火热证候在T2DM中的分布情况与导致其发生变化的相关因素,探索《内经》“壮火食气”理论,在T2DM病机假说中的科学性,丰富T2DM病机理论。
通过实验研究,探索清热益气药物黄连人参改善胰岛功能,促进p细胞损伤修复的作用机制,以期揭示清热益气治疗理论对β细胞保护的作用机理,从而验证“壮火食气”病机理论,丰富其科学内涵,为中医药治疗2型糖尿病提供新思路。
研究方法
1临床研究
通过横断面调查,观察T2DM患者一般情况,症状、代谢指标、胰岛功能等客观指标。对症状、证候要素进行频数统计、聚类及因子分析,比较不同证候要素患者的客观指标差异,并进行典型相关分析。通过7天纵向观察,比较两次证候调查结果与日间血糖波动的变化,对证候要素变化与血糖波动之间的相关性进行多元线性回归分析。
2实验研究
通过高热量高脂饲料喂养诱导GK大鼠,建立自发性T2DM大鼠模型,采用清热益气中药黄连人参对药进行干预,并设Wistar大鼠进行对照,观察黄连人参对代谢的调节作用,炎症因子水平及脂联素水平,进行胰腺病理学检测,观察其对胰岛结构的损伤修复作用,及TNF-α、脂联素受体、细胞凋亡因子在胰岛内表达。
研究结果
1临床研究
T2DM患者中,男性的发病高峰较女性早10岁左右,并且男性患者的年轻化趋势较女性更为严重,肥胖或超重在T2DM患者中普遍存在,与性别无关。T2DM早期并发症以DR、DPN、DN发生率较高,合并症中以高脂血症、高血压病、脂肪肝、冠心病出现率最高。
T2DM证候基本特点为：证候以虚实夹杂为主,单纯实证或单纯虚证相对少见；本虚证以气虚证、阴虚证为主,阳虚证相对较少,血虚证则未出现；标实证中,内热证普遍存在,痰湿证、血瘀证也较为突出,也有气郁证出现。内热证的表现形式多种多样,既可与痰湿、气郁、血瘀相兼为患,表现为湿热、郁热、瘀热,也可单独出现。其核心病位在肝胆、脾胃、胃肠,也可累及心与肺、肾。
HbAlc、LDL-C水平均与内热证相关,UAE水平与气虚证、痰湿证相关,TG水平既与内热证程度相关,又与痰湿证相关,UA、TC、HDL-C水平与痰湿证相关,BUN水平与阴虚证、阳虚证相关。内热证、痰湿证、血瘀证与胰岛功能关系密切,其中血糖水平及胰岛β细胞需求程度与内热证相关,胰岛p细胞功能、胰岛处置能力及胰岛素、C-肽水平与血瘀证、内热证均相关,胰岛素、C-肽水平、BMI及胰岛素抵抗水平、胰岛素敏感性痰湿证相关。
日间血糖波动也与证候变化相关,阴虚证积分变化与晚餐前血糖变化相关,阳虚证积分变化与晚餐后2小时血糖变化相关,气郁证积分变化与午餐前的血糖相关,而内热证积分变化则与三餐前后血糖变化均相关。
2实验研究
采用黄连人参治疗自发性T2DM大鼠模型4周,结果三组的体重、空腹胰岛素水平脂联素水平、胰岛素抵抗程度与胰岛素敏感性均无明显差异。模型组与黄连人参组餐后血糖、血脂、尿酸及血清超敏C反应蛋白水平均显著高于正常组,胰岛β细胞功能显著低于正常组,但两组间无明显差异。治疗后,黄连人参组的血清TNF-α水平及TNF-α、Bax在胰岛内表达均显著低于模型组与正常组无差异,而脂联素受体1的表达水平显著高于模型组,与正常组无差异,其胰岛结构紊乱程度也不及模型组严重。
研究结论
1临床研究
火热病机贯穿T2DM发生发展始终,是内热证候普遍存在的根本原因。
T2DM火热病机的实质是血糖、血脂代谢紊乱及胰岛功能损伤,内热既可与痰湿相合,又可与血瘀并见,均是导致T2DM发生发展的重要因素。
2实验研究
清热益气中药黄连人参的作用机制为下调促炎症因子及促凋亡因子在胰岛中的表达,上调脂联素受体在胰岛中的表达,从而促进胰岛β细胞的损伤修复。
Background
The incidence of diabetes (DM) is growing rapidly around the world. Type2diabetes (T2DM), which is the most common type of DM, is seriously threating human health. Traditional Chinese Medicine (TCM) has a great wealth of experience in treat with T2DM. As the dramatically change of modern lifestyle, the disease changes as well. The therapy of replenishing qi and nourishing yin, which guided by the traditional thinking often cannot achieve a satisfactory effect. Therefore, the TCM syndromes distribution, etiology and pathogenesis of T2DM need to be refreshed.
Objective
In order to be acquainted with the distribution of syndrome manifestations features of T2DM. and the correlation between the change of syndrome manifestations and objective indicators, especially the heat syndrome. So as to discover the mechanisms of heat-clearing and qi-replenishing drug. Coptis and ginseng in treating with T2DM and its action on beta-cell protection. Thus, verify the T2DM pathogenesis hypothesis "superheat consuming qi" to enrich T2DM pathogenesis theory, and provide new ideas for Chinese medicine treatment of type2diabetes.
Method
1Clinical research
Through the cross-sectional survey, we observed T2DM patients with general situation. symptoms, and objective indicators such as metabolic indicators, islet function. Analysis the symptoms and syndrome elements through frequeney cluster and factor analysis. Compare the differences of objective indicators among patients of different syndromes elements and do canonical correlation analysis as well. Through seven days longitudinal observation, compare the results of twice syndromes and blood glucose fluctuations, analysis the correlation between syndrome factors diversification and blood glucose fluctuations by multiple linear regression analysis.
2Experimental study
Set up the spontaneous T2DM rat model by GK rats induced by High-calorie high fat diet. using heat-clearing and qi-replenishing Chinese medicine Coptis and ginseng for intervention. and set Wistar rats as the control group, detecting the metabolic markers, inflammatory factors and adiponectin levels, as well as pancreatic pathology. So as to observe the islet structure damage repair effect of Coptis and ginseng, and TNF-alpha. adiponectin receptors apoptosis factor expression in islets.
Results
1Clinical research
The peak incidence of T2DM, men are about10years earlier than women.incidence of younger age in men are more serious than that in women. Over half of the T2DM patients are obese or overweight, regardless of gender. DR, DPN, DN are of the highest incidence of early T2DM complications. Hyperlipidemia, hypertension, fatty liver, and coronary heart disease are of the highest incidence of T2DM comorbidities.
The basic characteristics of T2DM syndromes are as follows:Syndromes mainly are deficiency-excess complications. Simple excess or simply deficiency syndromes are relatively rare; The main types of deficiency syndromes are qi and yin deficiency syndrome, and yang deficiency is relatively rare, while, blood deficiency syndrome does not appear in the survey. Meanwhile, for the excess syndromes, the internal heat syndromes are widespread, and the phlegm and blood stasis syndromes are also prominent, qi depression syndromes are exist as well. There are a variety of forms of the performance of the internal heat syndromes, which can appear with phlegm, qi depression or blood stasis simultaneously, and manifested as humid-heat, heat retention, stagnated heat, etc.,or appear alone as well. Its main loci are the liver and gallbladder, spleen and stomach, gastrointestinal, or involved with the heart, lung and kidney.
HbAlc, LDL-C levels are associated with the internal heat syndrome. UAE levels are associated with qi deficiency and phlegm syndrome. TG levels are associated with the degree of the internal heat syndrome as well as phlegm syndrome. UA.TC and HDI.-C levels are associated with phlegm. BUN levels are associated with yin and yang deficiency. There is close correlation among the internal heat, phlegm and blood stasis syndrome with islet function. Blood glucose levels and the extent of islet beta cells demand are related to the internal heat syndrome. The beta cell function, the deposition ability are both related to the blood stasis and the internal heat syndromes. BMI, insulin resistance level and insulin sensitivity are related to the phlegm syndrome.
The blood glucose fluctuations are also related with the change of syndromes. Yin deficiency syndrome change with the blood glucose levels of before dinner. Yang deficiency syndrome change with the blood glucose levels of2hours after dinner. Qi depression syndromes change with the blood glucose levels of before lunch. The internal heat syndrome change with the blood glucose levels of before and after every meal.
2Experimental study
Treat the spontaneous type2diabetic rats model with Coptis and ginseng treatment for4weeks, body weight, fasting insulin, adiponectin levels, insulin resistance and insulin sensitivity of the three groups had not significant difference.
The postprandial blood glucose, blood lipids, uric acid, and serum high sensitivity C reactive protein levels of the model group and the Coptis and ginseng group were significantly higher than for normal group, for islet beta cell function was significantly lower than normal group, but there is no significant difference between the two groups.
The serum TNF-alpha levels, islets TNF-alpha and Bax expression of Coptis and ginseng group were significantly lower than the model group, and had no difference with the normal group, and the expression of adiponectin receptor1in islet was significantly higher than that in the model group, and had no difference with the normal group.the degree of structural disorder of Islet is not that serious as the model group.
Conclusion
1Clinical research
It is the root of the reason that the heat pathogenesis goes throughout the whole course of T2DM. leading that the internal heat syndrome ubiquitous. The essence of T2DM heat pathogenesis is glucose metabolic disorder and which result in β-cell disfunction and apoptosis. The internal heat syndrome can conbine with either phlegm or blood stasis, which are both the important factors of T2DM progressing.
2Experimental study
The mechanism of Heat-clearing and qi-replenishing Chinese medicine Coptis and ginseng is that, down regulate the expression of proinflammatory cytokines and pro-apoptotic factors in islets, meanwhile increase the expression of adiponectin receptor in islets, thereby contributing to the islet beta-cell damage repair.
引文
[1]赵进喜,王世东,张丽芬.糖尿病相关中医病名考辨[J].辽宁中医杂志,2005,9：89-890.
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