發(fā)布時間：2018-06-10 10:17

  本文選題：代綜方 + 骨骼肌��； 參考：《中國中醫(yī)科學(xué)院》2017年博士論文

【摘要】：代謝綜合征(metabolic syndrome,MS)是指多種代謝異常聚集于同一個體的病理狀態(tài),可直接增加心血管疾病、2型糖尿病和全因死亡的風(fēng)險。目前其患病率迅猛增加,已成為影響全世界的一個重大公共衛(wèi)生問題。在美國,20歲以上的成年人中MS的患病率已由34%上升到44.2%;2009年國家健康與營養(yǎng)調(diào)查發(fā)現(xiàn),我國成人MS的患病率已達到18.2%;老年人群中MS患病粗率達25.5%。胰島素抵抗是指代謝器官或組織對胰島素的敏感性低于正常的一種病理生理狀態(tài),是MS腹型肥胖、高血糖、高血壓、血脂異常等代謝紊亂的共同病理基礎(chǔ)。骨骼肌是機體葡萄糖攝取和利用的主要場所,也是發(fā)生胰島素抵抗的重要場所。骨骼肌胰島素抵抗主要表現(xiàn)為胰島素刺激的葡萄糖攝取和利用能力下降,是導(dǎo)致全身胰島素抵抗及MS等代謝性疾病發(fā)病的原因之一。因此,調(diào)節(jié)骨骼肌葡萄糖代謝,改善骨骼肌胰島素抵抗對防治MS的發(fā)生發(fā)展具有重要意義。導(dǎo)師劉喜明教授認為,MS以腹型肥胖為核心組分,是由脂質(zhì)在腹部過度堆積所致,病位在中焦脾胃,根據(jù)“脾主散精”、“脾主肌肉四肢”理論,脂質(zhì)在腹部堆積,脾不散精,精微異常,游溢四肢是導(dǎo)致骨骼肌胰島素抵抗的重要病因。代綜方是導(dǎo)師基于二十余年臨床經(jīng)驗并結(jié)合現(xiàn)代臨床藥理研究所創(chuàng)制的治療MS痰熱互結(jié)證的基本方,主要由黃連、姜半夏、瓜萎皮等藥物組成。本課題組在國家“十二五”重大新藥創(chuàng)制課題“代綜方干預(yù)代謝綜合征早期糖脂代謝紊亂的新藥臨床前研究”中已開展了代綜方的藥學(xué)、藥效學(xué)、毒理學(xué)、臨床及基礎(chǔ)試驗研究,證實代綜方可減輕MS患者體重、改善糖脂代謝紊亂;促進脂肪細胞葡萄糖消耗和胞內(nèi)甘油三酯分解,改善脂質(zhì)合成與分解的動態(tài)平衡;下調(diào)C/EBP-α、PPAR-γ、FAS、ACC的基因表達抑制3T3-L1前脂肪細胞的分化;抑制油酸所致的肝細胞內(nèi)脂質(zhì)堆積。本研究將中醫(yī)理論與骨骼肌胰島素抵抗相結(jié)合,為代綜方治療MS提供進一步的證據(jù)支持。目的1.研究代綜方含藥血清對C2C12骨骼肌細胞葡萄糖代謝的影響,并從GLUT1、GLUT4的膜蛋白表達探討其作用機制。2.研究代綜方含藥血清對棕櫚酸誘導(dǎo)的C2C12骨骼肌細胞胰島素抵抗的影響,并從胰島素相關(guān)PI3K/AKT信號通路、AMPK通路及炎癥方面探討其作用機制。3.研究代綜方對自發(fā)性2型糖尿病KKAy小鼠糖脂代謝紊亂的影響。方法1.制備代綜方含藥血清及空白血清;采用MTT法檢測1%、5%、10%及20%代綜方含藥血清干預(yù)24h后C2C12細胞的活性,確立含藥血清濃度。2.以高、中、低劑量代綜方含藥血清(10%、5%、2.5%)分別干預(yù)C2C12細胞8h、16h及24h后,采用葡萄糖氧化酶法檢測葡萄糖消耗;以高劑量代綜方含藥血清干預(yù)C2C12細胞24h后,2-NBDG法檢測基礎(chǔ)狀態(tài)及胰島素刺激狀態(tài)下的C2C12細胞葡萄糖攝取。3.以高劑量代綜方含藥血清干預(yù)C2C12細胞24h后,采用Western blot檢測基礎(chǔ)狀態(tài)及胰島素刺激狀態(tài)下的GLUT1、GLUT4膜蛋白表達。4.以0.5mM棕櫚酸孵育C2C12骨骼肌細胞24h,制造骨骼肌細胞胰島素抵抗模型;采用2-NBDG法檢測胰島素抵抗C2C12細胞葡萄糖攝取;采用甘油三酯酶法測定胰島素抵抗C2C12細胞內(nèi)甘油三酯濃度。5.采用RT-PCR檢測胰島素抵抗C2C12細胞PI3K/AKT通路關(guān)鍵分子IRS-1、P13K、AKT、GLUT4的基因表達;檢測炎癥因子IL-6、TNF-α、NF-κB的基因表達。6.采用Western blot檢測胰島素抵抗C2C12細胞PI3K/AKT通路AKT、GSK-3β磷酸化蛋白及GLUT4膜蛋白表達,檢測AMPK通路AMPK、ACC磷酸化蛋白表達。7.采用DCFH-DA熒光探針孵育胰島素抵抗C2C12細胞20min,分別應(yīng)用熒光顯微鏡、流式細胞儀檢測DCF熒光強度,根據(jù)其熒光強度判斷ROS水平。8.采用NF-κB激活-核轉(zhuǎn)運檢測試劑盒檢測胰島素抵抗C2C12細胞NF-κB核轉(zhuǎn)運。9.選用8周齡KKAy小鼠高脂飼料喂養(yǎng),篩選空腹血糖13.9mmol/L的小鼠60只,按體重隨機分為5組:模型對照組(Con)、二甲雙胍組(Met,200mg/kg/天)、代綜方高劑量組(DZFh,2000mg/kg/天)、代綜方中劑量組(DZFm,1500mg/kg/天)、代綜方低劑量組(DZFl,1000mg/kg/天);另取8周齡C57BL/6J小鼠8只作為正常對照組(Nor)。每日上午灌胃給藥一次,為期8周,模型對照組與正常對照組給予相同劑量的無菌水。每周檢測小鼠進食量、體重、空腹血糖,第8周檢測小鼠糖耐量。實驗結(jié)束后取材,檢測血糖、血脂4項、血清胰島素并計算胰島素敏感指數(shù)(QUICKI)。10.每組隨機選取4只小鼠,分離骨骼肌,常規(guī)石蠟包埋切片,免疫組化檢測小鼠骨骼肌GLUT4蛋白表達。結(jié)果1.與正常對照組相比,空白血清組及不同濃度代綜方含藥血清組細胞存活率無明顯差異(P0.05)。2.與空白血清組比較,代綜方含藥血清干預(yù)8h后,高、中劑量組C2C12細胞葡萄糖消耗即顯著增加(P0.05),增加幅度分別為22.54%、18.75%,干預(yù)16h、24h后,高、中、低劑量組C2C12細胞葡萄糖消耗均顯著增加(P0.05),三組含藥血清相比,高劑量組作用效果最佳;以高劑量代綜方含藥血清干預(yù)C2C12細胞24h后檢測葡萄糖攝取,與空白血清組比較,基礎(chǔ)狀態(tài)下,代綜方含藥血清高劑量組熒光強度增加19.88%,胰島素刺激狀態(tài)下,熒光強度增加9.54%,差異均有統(tǒng)計學(xué)意義(P=0.041,P=0.030)。3.以高劑量代綜方含藥血清干預(yù)C2C12細胞24h,基礎(chǔ)狀態(tài)下,可顯著增加 C2C12 細胞 GLUT1、GLUT4 膜蛋白表達(P=0.008,P=0.004),與空白血清組相比,分別增加30.98%、59.07%;胰島素刺激狀態(tài)下,可顯著增加GLUT1膜蛋白表達(P=0.000),與空白血清組相比,增加42.26%。4.棕櫚酸孵育C2C12細胞24h后,胰島素刺激下的葡萄糖攝取量下降30.72%,產(chǎn)生胰島素抵抗;代綜方含藥血清干預(yù)胰島素抵抗C2C12細胞24h后,葡萄糖攝取量增加,其中高、中劑量組葡萄糖攝取量分別增加20.62%、13.27%,差異顯著(P=0.001,P=0.039);棕櫚酸孵育 C2C12 細胞24h后,細胞內(nèi)甘油三酯濃度顯著增加(P=0.000),高劑量代綜方干預(yù)后,甘油三酯濃度顯著降低(P=0.004)。5.高劑量代綜方含藥血清干預(yù)胰島素抵抗C2C12細胞24h后,可上調(diào)AKT mRNA、GLUT4mRNA 的表達(P=0.042,P=0.041);增加 p-AKT、p-GSK-3β蛋白表達(P=0.002,P=0.000),增加GLUT4膜蛋白表達(P=0.001)。6.高劑量代綜方含藥血清干預(yù)胰島素抵抗C2C12細胞24h后,可增加p-AMPK及 p-ACC 蛋白表達(P=0.006,P=0.012)。7.高劑量代綜方含藥血清干預(yù)胰島素抵抗C2C12細胞24h后,可降低IL-6mRNA、TNF-αmRNA 表達(P=0.003,P=0.013),降低 ROS 水平(P0.05),降低 NF-κBmRNA 表達及 NF-κB 核轉(zhuǎn)運(P=0.002)。8.代綜方各劑量組KKAy小鼠的體重與模型組相比雖無明顯差異,但體重增長呈下降趨勢;給藥過程中,與模型組相比,代綜方各劑量組KKAy小鼠空腹血糖呈下降趨勢,給藥6周時,代綜方高劑量組血糖下降15.19%(P0.05),給藥8周時,代綜方中、高劑量組血糖分別下降17.46%、15.29%(P0.05);與模型組相比,代綜方高劑量組KKAy小鼠的糖耐量異常有明顯緩解(P0.05);與模型組相比,代綜方高劑量組TC水平降低11.33%(P0.05),代綜方高劑量及中劑量組TG水平分別下降28.78%、18.80%(P0.05),代綜方各劑量組HDL-C水平無明顯差異(P0.05);代綜方高劑量組LDL-C的水平降低25.20%(P0.05);代綜方高、中劑量組空腹胰島素水平明顯下降(P0.05),QUICKI指數(shù)顯著增加(p0.05)。9.與模型組相比,代綜方高劑量組骨骼肌GLUT4蛋白表達顯著增加(P=0.003)。結(jié)論1.代綜方含藥血清濃度在20%以內(nèi)時,對C2C12細胞活性無明顯影響;代綜方含藥血清可增加骨骼肌細胞葡萄糖消耗和攝取,其作用機制可能與增加GLUT1、GLUT4膜蛋白表達相關(guān)。2.代綜方含藥血清可改善C2C12骨骼肌細胞胰島素抵抗,其作用機制可能與上調(diào)PI3K/AKT通路中關(guān)鍵分子AKT的基因表達,增加AKT蛋白磷酸化,進而促進GLUT4基因表達及膜轉(zhuǎn)位并降低糖原合成激酶GSK3活性;激活A(yù)MPK信號通路;抑制骨骼肌細胞炎癥有關(guān)。3.代綜方可改善KKAy小鼠糖脂代謝紊亂,增加胰島素敏感性,其作用機制可能與增加骨骼肌GLUT4蛋白表達相關(guān)。
[Abstract]:Metabolic syndrome (MS) refers to the pathological condition of various metabolic abnormalities that accumulate in the same individual. It can directly increase the risk of cardiovascular disease, type 2 diabetes and all causes of death. At present, the prevalence rate has increased rapidly. It has become a major public health problem affecting the whole world. In the United States, among adults over 20 years old, MS The prevalence rate has risen from 34% to 44.2%. In 2009, the national health and nutrition survey found that the prevalence rate of adult MS in China has reached 18.2%, and the MS prevalence of 25.5%. insulin resistance in the elderly is a pathological condition of metabolic organ or tissue sensitivity to insulin lower than normal, and it is MS abdominal obesity, hyperglycemia, and hypertension. Skeletal muscle is the main site of glucose uptake and utilization, and it is also an important place for insulin resistance. The insulin resistance of skeletal muscle is mainly manifested by insulin stimulation of glucose uptake and utilization ability, which leads to systemic insulin resistance and MS metabolic diseases. One of the causes of the disease is that it is of great significance to regulate the glucose metabolism of skeletal muscle and improve the insulin resistance of skeletal muscles to prevent and control the occurrence and development of MS. Professor Liu Ximing of the tutor believes that MS is the core component of abdominal obesity, which is caused by excessive accumulation of lipids in the abdomen, the position of the disease in the middle of the spleen and the stomach, and "spleen main muscle", "spleen main muscle" Extremities "theory, lipid accumulation in the abdomen, spleen inseminal essence, subtle abnormalities, and overflowing extremities is an important cause of insulin resistance in skeletal muscle. The agent is based on twenty years of clinical experience combined with modern clinical pharmacology research to treat MS phlegm heat exchange syndrome, mainly by Coptis chinensis, Jiang Banxia, melon wilt skin and other drugs. The research group has carried out the pharmacology, pharmacodynamics, toxicology, clinical and basic test of the new drug in the national "12th Five-Year" major new drug creation subject, "the new drug in the preclinical study of the early glycolipid metabolic disorder of metabolic syndrome." it has been proved that the agent can reduce the weight of MS patients and improve the disorder of glycolipid metabolism. Promote glucose consumption and intracellular triglyceride decomposition in adipocytes and improve the dynamic balance of lipid synthesis and decomposition; down regulation of C/EBP- alpha, PPAR- gamma, FAS, ACC gene expression inhibits the differentiation of 3T3-L1 preadipocytes and inhibits the accumulation of lipid in liver cells induced by oleic acid. To provide further evidence support for the treatment of MS. Objective 1. to study the effect of the serum on the glucose metabolism of C2C12 skeletal muscle cells, and to explore the effect of.2. on the insulin resistance of the skeletal muscle cells induced by palmitic acid, and from the insulin phase, from the expression of the membrane protein expression of GLUT1 and GLUT4. The effect of PI3K/AKT signaling pathway, AMPK pathway and inflammation on the effect of.3. on the glucose and lipid metabolism disorder of spontaneous type 2 diabetes KKAy mice. Method 1. to prepare the serum and blank sera of the synthesizer, and to detect the activity of C2C12 cells after the intervention of 24h in 1%, 5%, 10% and 20% generation with MTT. Serum concentration of.2. in high, middle and low doses (10%, 5%, 2.5%) interfered with C2C12 cells 8h, 16h and 24h respectively. Glucose oxidase method was used to detect glucose consumption, and C2C12 cell 24h was intervened by high dose heald serum containing serum, and 2-NBDG assay was used to detect C2C12 cell glucose uptake under the condition of insulin stimulation. After taking.3. to intervene the C2C12 cell 24h with high dose of the drug containing serum, Western blot was used to detect the basic state and GLUT1 in the state of insulin stimulation. The GLUT4 membrane protein expressed.4. with 0.5mM palmitic acid incubating C2C12 skeletal muscle cells 24h, producing insulin resistance model of skeletal muscle cells, and using 2-NBDG method to detect insulin resistance to Staphylococcus aureus cells. Glucose uptake and determination of triglyceride concentration in insulin resistance C2C12 cells by triglyceride method.5. using RT-PCR to detect the gene expression of IRS-1, P13K, AKT, GLUT4, the key molecules of the PI3K/AKT pathway of insulin resistance C2C12 cells, and the detection of inflammatory factors IL-6, TNF- alpha. Cell PI3K/AKT pathway AKT, GSK-3 beta phosphorylated protein and GLUT4 membrane protein expression, AMPK pathway AMPK, ACC phosphorylated protein expression.7. use DCFH-DA fluorescence probe to incubate insulin resistance C2C12 cell 20min. Fluorescence microscopy, flow cytometry, respectively, detect DCF fluorescence intensity. Activation nuclear transfer detection kit was used to detect the NF- kappa B nuclear transport of insulin resistance C2C12 cells, and 60 mice were fed with high fat diet of KKAy mice of 8 weeks old, and 60 mice were selected for screening empty fasting blood glucose 13.9mmol/L. They were randomly divided into 5 groups according to weight: model control group (Con), metformin group (Met, 200mg/ kg/ days), and the generation of high dose group (DZFh, 2000mg/kg/ days), and the generation side. Medium dose group (DZFm, 1500mg/kg/ days), lower dose group (DZFl, 1000mg/kg/ days), and 8 C57BL/6J mice of 8 weeks age as normal control group (Nor). Every morning gavage was given for 8 weeks. The model control group was given the same dose of aseptic water with the normal control group. The mice intake, body weight, fasting blood glucose and eighth week test were detected weekly. After the experiment, the blood glucose, blood lipid 4 items, the serum insulin and the insulin sensitivity index (QUICKI).10. were selected and 4 mice were randomly selected to separate the skeletal muscle, the routine paraffin embedded section and the immunohistochemical detection of GLUT4 protein in the skeletal muscle of mice were detected. Results 1. compared with the normal control group, the blank sera group and the normal control group were no more than the normal control group. Compared with the blank sera group, there was no significant difference in the cell survival rate of the serum group with the same concentration (P0.05).2. and the blank sera group. After the intervention of 8h, the glucose consumption of the C2C12 cells in the middle dose group increased significantly (P0.05), the increase was 22.54%, 18.75%, and after 24h, the glucose consumption in the high, middle and low dose groups of C2C12 cells was all after 24h. Significantly increased (P0.05), compared with the three groups of serum containing drugs, the high dose group had the best effect, and the glucose uptake was detected after the intervention of the C2C12 cell 24h in the high dose heald prescription serum. Compared with the blank sera group, the fluorescence intensity increased by 19.88% in the high dose group containing the heald prescription serum, and the fluorescence intensity increased by 9.5 under the state of insulin stimulation. 4%, the difference was statistically significant (P=0.041, P=0.030).3. was used to interfere with 24h in C2C12 cells with high dose of agent serum, which could significantly increase the GLUT1, GLUT4 membrane protein expression (P=0.008, P=0.004) in C2C12 cells, and increased by 30.98%, 59.07% respectively compared with the blank sera group, and the GLUT1 membrane protein could be significantly increased under the condition of insulin stimulation. Expression (P=0.000), compared with the blank sera group, after increasing 42.26%.4. palmitic acid to incubate C2C12 cell 24h, the glucose uptake under insulin stimulation decreased by 30.72% and produced insulin resistance. The glucose uptake increased after the intervention of the insulin resistance C2C12 cell 24h by the heald serum containing drug serum, and the glucose uptake in the medium dose group increased respectively. Adding 20.62%, 13.27%, the difference was significant (P=0.001, P=0.039); after the palmitic acid incubated 24h, the intracellular triglyceride concentration increased significantly (P=0.000). The concentration of triglyceride decreased significantly (P=0.004) (P=0.000), and the high dose of the triglyceride concentration was significantly decreased (P=0.004), and the high dose of the.5. in the high dose heald serum intervened the 24h of the insulin resistance of C2C12 cells, and the AKT mRNA could be up-regulated. GLUT4mRNA Expression (P=0.042, P=0.041); increase p-AKT, p-GSK-3 beta protein expression (P=0.002, P=0.000), increase GLUT4 membrane protein expression (P=0.001) and.6. high dose heald prescription containing serum intervention of insulin resistance C2C12 cell 24h, can increase the expression of p-AMPK and protein expression. After 24h, IL-6mRNA, TNF- alpha mRNA expression (P=0.003, P=0.013), ROS level (P0.05), NF- kappa BmRNA expression and NF- kappa B nuclear transfer were reduced, although there was no significant difference between the model group and the model group, the weight gain decreased. The fasting blood glucose of KKAy mice in each dose group decreased, and the blood glucose decreased by 15.19% (P0.05) in the high dose group at 6 weeks. The glucose tolerance of the high dose group decreased by 17.46% and 15.29% (P0.05) in the high dose group at 8 weeks. Compared with the model group, the glucose tolerance abnormality in the high dose group of KKAy mice was significantly relieved (P0.05). Compared with the model group, the high dose group of the high dose group was compared with the model group. The level of TC in the high dose group was reduced by 11.33% (P0.05), and the level of TG in the high and middle dose groups of the synthesizer decreased by 28.78%, 18.80% (P0.05), and there was no significant difference in HDL-C level in each dose group of the generation (P0.05); the level of LDL-C in the high dose group was decreased by 25.20% (P0.05), and the level of fasting insulin in the medium dose group was significantly lower (P0.05). The QUICKI index increased significantly (P0.05).9. compared with the model group, the expression of GLUT4 protein in the skeletal muscle of the high dose group was significantly increased (P=0.003). Conclusion the serum concentration of the 1. generation heald prescription was less than 20%, and the serum glucose consumption and intake of skeletal muscle cells could be increased. It can improve the insulin resistance of C2C12 skeletal muscle cells with the increase of GLUT1 and GLUT4 membrane protein expression, which may improve the gene expression of the key molecule AKT in the PI3K/AKT pathway, increase the phosphorylation of the AKT protein, and then promote the expression of GLUT4 gene and the translocation of the membrane and reduce the GSK3 activity of the glycogen kinase, and stimulate the activity of the glycogen kinase. Living AMPK signaling pathway, inhibiting the inflammation of skeletal muscle cells related to.3. generation can improve the metabolic disorder of glucose and lipid in KKAy mice and increase the sensitivity of insulin. The mechanism may be related to the increase of GLUT4 protein expression in skeletal muscle.
【學(xué)位授予單位】：中國中醫(yī)科學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R259

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