發(fā)布時間：2018-07-25 10:46

【摘要】：糖尿病是嚴重危害人類健康的慢性非傳染性疾病,中國的2型糖尿病發(fā)病率呈現(xiàn)出逐年上升的趨勢,成為糖尿病患病大國,糖尿病的防治研究任重道遠。胰島素抵抗是2型糖尿病發(fā)病的重要機制之一,改善胰島素抵抗是臨床治療糖尿病的主要策略。植物化學(xué)物具有抗炎、抗氧化、抗癌等多種生物學(xué)活性,在疾病的防治中有著重要應(yīng)用價值。其中類黃酮化合物因其具有降血糖、低毒副作用的功效而備受關(guān)注,但其具體機制尚不明了。過氧化物酶體增殖物激活受(peroxisome proliferator-activated receptor,PPAR)-γ參與調(diào)節(jié)機體糖脂代謝,是臨床研發(fā)抗糖尿病藥物的重要靶點。其中胰島素增敏劑噻唑烷二酮類(Thiazolidinedione,TZD)藥物如羅格列酮(Rosiglitazone,ROSI)雖具有良好降糖效果,但其最為PPARγ的一種完全激動劑可導(dǎo)致成脂增加和肥胖。研究發(fā)現(xiàn)類黃酮化合物能通過部分激活PPARγ增強胰島素敏感性的同時,減少成脂、肥胖和水腫等諸多羅格列酮藥物的副作用。二氫楊梅素(Dihydromyricetin,DHM)作為一種類黃酮化合物,具有抗炎、抗氧化、抗酒精性中毒和抗腫瘤等多種生物學(xué)活性,也有研究報道其具有降血糖作用,但具體機制還有待進一步闡明。研究發(fā)現(xiàn),PPARγ的磷酸化與胰島素抵抗的發(fā)生密切相關(guān)。抑制PPARγ273位點絲氨酸的磷酸化是PPARγ的配體發(fā)揮降糖作用的主要機制。細胞外信號調(diào)節(jié)蛋白激酶(Extracellular Regulating Kinase,ERK)和細胞周期蛋白依賴性激酶(Cyclin-dependent Kinase,CDK5)都能介導(dǎo)PPARγ273位點的磷酸化,導(dǎo)致肥胖相關(guān)的胰島素抵抗的發(fā)生。抑制MEK/ERK通路能顯著提高動物胰島素敏感性。多種類黃酮化合物均被證實能抑制MEK/ERK信號通路促進腫瘤細胞凋亡�；诮Y(jié)構(gòu)-效應(yīng)關(guān)系理論推理和本課題組前期計算機模擬分子對接發(fā)現(xiàn)DHM能直接與PPARγ的配體結(jié)合區(qū)結(jié)合,我們推測類黃酮化合物DHM可能通過調(diào)控MEK/ERK,抑制PPARγ273位點的磷酸化,進而提高胰島素敏感性,有效降低血糖。實驗方法:本研究包括體內(nèi)動物實驗和離體細胞實驗兩部分。以Zucker Diabetic Fatty(ZDF)糖尿病模型大鼠和3T3-L1脂肪細胞為研究對象。1.實驗分組:健康對照組ZL大鼠,ZDF對照組,DHM(50mg/kg)組,DHM(100mg/kg)組,DHM(200mg/kg)組,羅格列酮(4mg/kg)組;每日灌胃,共8周。隔日記錄體重,每周測量進食量和空腹血糖、胰島素、胰高血糖素水平,第0、4、8周測量血脂水平、脂聯(lián)素和FGF21水平,實驗第7周進行口服葡萄糖耐量實驗(OGTT),第8周進行胰島素耐量實驗(ITT)。2.干預(yù)第7周,活體小動物CT成像分析大鼠體成分組成。3.實驗結(jié)束后取肝臟、胰腺、腎臟、脂肪組織進行油紅O染色、組織化學(xué)染色或免疫組織化學(xué)染色。Western Blot測定ZDF大鼠脂肪組織PPARγ蛋白表達及磷酸化。4.采用地塞米松誘導(dǎo)建立3T3-L1脂肪細胞的胰島素抵抗模型,分析DHM對細胞成脂分化、糖攝取能力的影響。ELISA檢測脂肪因子的分泌。5.Western Blot測定脂肪細胞PPARγ磷酸化水平及其上游調(diào)控激酶ERK/CDK5的蛋白表達水平。使用PPARγ抑制劑GW9662阻斷PPARγ活性,觀察其對DHM對脂肪細胞糖攝取和脂聯(lián)素分泌的影響;用MEK抑制劑PD98059阻斷ERK活性,對比研究DHM和MEK抑制劑的作用效應(yīng)。主要實驗結(jié)果:1.DHM降低ZDF大鼠空腹血糖,提高胰島素敏感性。中、高劑量(100mg/kg和200mg/kg)DHM組大鼠空腹血糖顯著低于ZDF對照組,低劑量(50 mg/kg)DHM維持大鼠空腹血糖低于10mM到實驗第7周。第7周口服葡萄糖耐量實驗(Oral Glucose Tolerance Test,OGTT)顯示,3個劑量DHM組口服葡萄糖30min后血糖值均顯著低于ZDF對照組;第8周胰島素耐量實驗(Insulin Tolerance Test,ITT)顯示,中、高劑量(100mg/kg和200mg/kg)DHM組在注射胰島素30min后,血糖顯著低于ZDF對照組。2.DHM改善糖尿病大鼠血脂水平,不引起動物體重增加。DHM顯著降低血清TG和LDL-C水平,升高HDL-C水平。干預(yù)第8周末,DHM組大鼠體重增加量比羅格列酮組降低了56%~74%。3.DHM對糖尿病大鼠的肝臟、胰腺和腎臟有保護作用。DHM降低肝細胞脂質(zhì)沉積、維持肝小葉正常形態(tài)、減緩肝脂肪樣變。DHM增加胰島體積,維持胰島形態(tài)完整性,提高β細胞的胰島素含量。DHM顯著降低腎間質(zhì)炎細胞浸潤,減少腎小球系膜基質(zhì)增生。4.DHM降低糖尿病大鼠的脂肪組織含量,減小脂肪細胞體積,增加脂聯(lián)素分泌。體成分組成顯示,與羅格列酮相比DHM顯著降低大鼠總脂肪和內(nèi)臟脂肪含量。脂肪組織油紅O染色顯示,ZDF對照大鼠皮下、內(nèi)臟脂肪細胞體積顯著增大,DHM降低脂肪細胞體積,其皮下、內(nèi)臟脂肪細胞大小與ZL健康對照組無顯著差異。第0,4,8周分別進行血清脂聯(lián)素水平檢測,ZDF對照組脂聯(lián)素水平進行性下降,而DHM顯著升高血清脂聯(lián)素水平,與ZL健康對照組無明顯差異。5.體內(nèi)和體外實驗Western Blot結(jié)果均顯示,DHM抑制脂肪組織和細胞中PPARγ273位點絲氨酸磷酸化,而且DHM抑制PPARγ磷酸化能力優(yōu)于羅格列酮。此外,DHM還顯著降低調(diào)節(jié)PPARγ磷酸化的激酶ERK和CDK5的活性。6.在地塞米松建立的3T3-L1脂肪細胞胰島素抵抗模型中,DHM劑量依賴性的顯著提高細胞的糖攝取能力,增加脂肪細胞分泌脂聯(lián)素和FGF21水平。PPARγ抑制劑GW9662阻斷了DHM提高脂肪細胞糖攝取和增加分泌脂聯(lián)素、FGF21的能力。DHM表現(xiàn)出與MEK抑制劑PD98059相同的提高脂肪細胞糖攝取和促分泌脂聯(lián)素、FGF21的作用,且兩者聯(lián)用具有協(xié)同效應(yīng)。結(jié)論:1.DHM能降低ZDF糖尿病大鼠空腹血糖,減輕胰島素抵抗,改善血脂水平。此外,DHM減少肝臟脂質(zhì)沉積,增加胰腺組織胰島的體積和胰島素含量,緩解腎間質(zhì)炎細胞浸潤和腎小球系膜基質(zhì)增生。研究同時發(fā)現(xiàn),長期使用DHM并不引起動物體重的過多增加。2.體內(nèi)實驗中,DHM降低糖尿病大鼠體脂含量,縮小脂肪細胞體積,增加脂肪細胞脂聯(lián)素水平。體外實驗中利用地塞米松建立3T3-L1脂肪細胞胰島素抵抗模型,發(fā)現(xiàn)DHM提高胰島素抵抗的3T3-L1脂肪細胞糖攝取能力,促進脂肪細胞分泌脂聯(lián)素和FGF21。3.通過調(diào)節(jié)MEK/ERK信號通路抑制PPARγSer273磷酸化是DHM降低胰島素抵抗的主要作用機制,且DHM和MEK抑制劑協(xié)同作用,提高脂肪細胞胰島素敏感性。綜上所述,本研究進一步揭示了二氫楊梅素(DHM)改善胰島素抵抗的分子作用機制,首次提出抑制PPARγ273位點絲氨酸的磷酸化是DHM的作用機制,為將藤茶或其提取物DHM應(yīng)用于臨床糖尿病的防治提供了重要的科學(xué)依據(jù)。
[Abstract]:Diabetes is a chronic non communicable disease which seriously endangers human health. The incidence of type 2 diabetes in China is increasing year by year. It has become a major diabetes country. The study of diabetes prevention is a long way to go. Insulin resistance is one of the important mechanisms of the onset of type 2 diabetes. Improving insulin resistance is a clinical treatment for diabetes. Major strategies. Phytochemicals have many biological activities, such as anti-inflammatory, antioxidant and anticancer, which have important application value in the prevention and treatment of diseases. Among them, the flavonoids have attracted much attention because of their hypoglycemic and low toxic and side effects, but the specific mechanisms are still unknown. Peroxisome proliferators are activated by (peroxisome prolif). Erator-activated receptor, PPAR) - gamma is an important target in the clinical research and development of antidiabetic drugs. The insulin sensitizer (Thiazolidinedione, TZD), such as Rosiglitazone, ROSI, has a good hypoglycemic effect, but a complete agonist of the most PPAR gamma can lead to a complete agonist of PPAR gamma. The study found that flavonoids can reduce the side effects of many rosiglitazone drugs, such as lipid, obesity, and edema, by partially activating PPAR gamma. Two Dihydromyricetin (DHM), as a kind of flavonoid compound, has anti-inflammatory, antioxidant, anti alcohol poisoning, and swelling resistance. Many biological activities, such as tumor, have also been reported to have hypoglycemic effect, but the specific mechanism remains to be further elucidated. Studies have found that the phosphorylation of PPAR gamma is closely related to the occurrence of insulin resistance. The inhibition of the phosphorylation of serine at the PPAR gamma 273 site is the main mechanism of PPAR gamma ligand playing the hypoglycemic effect. Protein kinase (Extracellular Regulating Kinase, ERK) and cyclin dependent kinase (Cyclin-dependent Kinase, CDK5) can mediate phosphorylation of PPAR gamma 273 site, leading to the occurrence of obesity related insulin resistance. Inhibition of the MEK/ERK pathway can significantly increase the insulin sensitivity of animals. Inhibition of MEK/ERK signaling pathway to promote apoptosis of tumor cells. Based on the theoretical reasoning of structural effect relationship and the docking of DHM to the ligand binding area of PPAR gamma, we speculate that the flavonoid compound DHM may improve the islet by regulating MEK/ERK, inhibiting the phosphorylation of the PPAR gamma 273 site and thus improving the islets of the islets. Zucker Diabetic Fatty (ZDF) diabetic model rats and 3T3-L1 adipocytes were divided into groups of.1. experimental groups: healthy control group ZL rats, ZDF pairs, DHM (50mg/kg), DHM (100mg/kg) group, 3T3-L1 group, The group of rosiglitazone (4mg/kg) group was administered daily for 8 weeks. The body weight was recorded every other day, daily intake of food and fasting blood glucose, insulin, glucagon level, serum lipid levels, adiponectin and FGF21 levels, oral glucose tolerance test (OGTT) for the first seventh weeks, and eighth weeks of insulin tolerance test (ITT).2. intervention for seventh weeks were performed. Liver, pancreas, kidney, and adipose tissue were stained with oil and red O after the CT imaging analysis of the body composition of the rat body. The expression of PPAR gamma protein in the adipose tissue of ZDF rats was determined by histochemical staining or immunohistochemical staining with.Western Blot, and the phosphorylated.4. was induced by dexamethasone to establish the insulin of 3T3-L1 adipocytes. Resistance model, analysis of the effect of DHM on the differentiation of cells and the effect of sugar uptake..ELISA detected the secretion of adipokine by.5.Western Blot and the level of PPAR gamma phosphorylation in adipocytes and the protein expression level of the upstream regulated kinase ERK/CDK5. The PPAR gamma inhibitor GW9662 was used to block the PPAR gamma activity and to observe the uptake of sugar in DHM to the fat cells and the glucose uptake by DHM. The effect of adiponectin secretion; blocking ERK activity with MEK inhibitor PD98059 and comparing the effect of DHM and MEK inhibitors. Main experimental results: 1.DHM reduced fasting blood glucose in ZDF rats and increased insulin sensitivity. In the high dose (100mg/kg and 200mg/kg) DHM group, the fasting blood sugar of the rats was significantly lower than that in the ZDF control group, and the low dose (50 mg/kg) was maintained. The fasting blood glucose in rats was lower than 10mM to seventh weeks. The oral glucose tolerance test (Oral Glucose Tolerance Test, OGTT) at seventh weeks showed that the blood glucose values of the 3 DHM groups after oral glucose 30min were significantly lower than those in the ZDF control group; eighth weeks of insulin tolerance test (Insulin Tolerance Test) showed that the high dose (Insulin Tolerance Test) group was in the high dose group. After the injection of insulin 30min, the blood glucose was significantly lower than that of the ZDF control group.2.DHM to improve the blood lipid level of the diabetic rats, and no increase of the body weight.DHM significantly decreased the level of serum TG and LDL-C and increased the level of HDL-C. At the end of the eighth weekend, the weight gain of DHM group was lower than that of the rosiglitazone group, and the liver and pancreas of diabetic rats were lower than that of the rosiglitazone group. The protective effect of.DHM and kidney can reduce the lipid deposition of liver cells, maintain the normal form of hepatic lobule, slow down the liver fat like changes, increase the islet volume, maintain the integrity of the islet, improve the insulin content of beta cells, reduce the infiltration of renal interstitial inflammatory cells, reduce the glomerular mesangial matrix hyperplasia and reduce the fat of the diabetic rats by reducing the.4.DHM of the glomerular mesangial matrix, and reducing the fat of the diabetic rats. Tissue content reduced fat cell volume and increased adiponectin secretion. Body composition showed that DHM significantly reduced total fat and visceral fat content in rats compared with rosiglitazone. Fat tissue oil red O staining showed that ZDF control rats were subcutaneous, visceral adipocyte volume increased significantly, DHM decreased fat cell volume, and subcutaneous, visceral fat was thin. There was no significant difference between the cell size and the ZL health control group. The serum adiponectin level was detected at week 0,4,8, and the level of adiponectin in the ZDF control group decreased, while the DHM significantly increased the serum adiponectin level, and there was no significant difference between the.5. body and the ZL healthy control group. The results of Western Blot in both in vivo and in vitro showed that DHM inhibited adipose tissue and cells in the cells. PPAR gamma 273 site serine phosphorylation, and the ability of DHM to inhibit PPAR gamma phosphorylation is superior to rosiglitazone. In addition, DHM also significantly reduces the activity.6. regulating PPAR gamma phosphorylation of kinase ERK and CDK5 in the insulin resistance model established by dexamethasone in the insulin resistance model of dexamethasone. The dose dependence of DHM increases the sugar uptake and increase of cells significantly. Adipocytes secrete adiponectin and FGF21 level.PPAR gamma inhibitor GW9662 block DHM increase sugar uptake and increase the secretion of adiponectin. FGF21's ability.DHM shows the same as MEK inhibitor PD98059 to increase fat cell sugar uptake and promote division of secretin, FGF21, and both have synergistic effect. Conclusion: 1.DHM can be used. Reducing the fasting blood glucose, reducing insulin resistance and improving blood lipid levels in ZDF diabetic rats. In addition, DHM reduces liver lipid deposition, increases the volume and insulin content of pancreatic islets, alleviates the infiltration of renal interstitial inflammation and glomerular mesangial matrix hyperplasia. The study also shows that long-term use of DHM does not cause excessive increase in animal weight. In the.2. experiment, DHM reduced the body fat content of diabetic rats, reduced the volume of adipocyte and increased adipocyte adiponectin level. In vitro, the insulin resistance model of 3T3-L1 adipocytes was established by dexamethasone. It was found that DHM increased the glucose uptake ability of 3T3-L1 adipocytes in insulin resistance, and promoted adipocytes to secrete adiponectin and FG. F21.3. by regulating the MEK/ERK signaling pathway to inhibit PPAR gamma Ser273 phosphorylation is the main mechanism of DHM to reduce insulin resistance, and DHM and MEK inhibitors synergistically to increase the insulin sensitivity of adipocytes. To sum up, this study further revealed the molecular mechanism of two hydrogen myricetin (DHM) to improve insulin resistance, for the first time The inhibition of the phosphorylation of serine at PPAR gamma 273 site is the mechanism of DHM, which provides an important scientific basis for the application of rattan tea or its extract DHM in the prevention and control of clinical diabetes.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R285.5

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9 孫莉;尚進林;梁浩;程焱;;PPAR全激動劑對小鼠局灶性腦缺血再灌注損傷的保護作用[A];第十一屆全國神經(jīng)病學(xué)學(xué)術(shù)會議論文匯編[C];2008年

10 ;Endothelial PPARγmediates anti-inflammatory actions of rosiglitazone through dissociation of NF-κB[A];中國生理學(xué)會心血管生理學(xué)術(shù)研討會論文集[C];2011年

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1 徐錚奎;發(fā)現(xiàn)PPAR拮抗劑[N];醫(yī)藥經(jīng)濟報;2012年

2 曾凡新邋林敏;PPAR激動劑類抗糖尿病藥研發(fā)喜憂參半[N];中國醫(yī)藥報;2007年

3 ;胰島素小常識[N];保健時報;2004年

4 ;胰島素抵抗，，怎么辦？[N];解放日報;2004年

5 中南大學(xué)湘雅二醫(yī)院老年病科副教授 陳化;什么是“胰島素抵抗”[N];健康報;2001年

6 張家慶 （教授）;適度鍛煉身體改善胰島素抵抗[N];上海中醫(yī)藥報;2003年

7 本報記者 韓曉英;注射胰島素會成癮嗎[N];中國中醫(yī)藥報;2002年

8 張怡梅 劉 斌;惡性腫瘤與胰島素抵抗[N];中國中醫(yī)藥報;2003年

9 健康時報特約記者 陳錦屏;胖人易發(fā)“胰島素抵抗”[N];健康時報;2007年

10 殳雪怡;胰島素抵抗 有辦法“抵抗”嗎[N];家庭醫(yī)生報;2007年

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1 劉蕾;二氫楊梅素通過抑制PPARγ磷酸化改善胰島素抵抗的作用及機制研究[D];第三軍醫(yī)大學(xué);2017年

2 劉炳婷;SUMO特異性蛋白酶1調(diào)控脂肪形成的作用及分子機制[D];上海交通大學(xué);2014年

3 陳宏;巨噬細胞PPARγ對皮膚傷口愈合的作用研究[D];第三軍醫(yī)大學(xué);2015年

4 韓晶;PPARγ在腦缺血再灌注損傷和過氧化氫損傷中的調(diào)控機制研究[D];天津醫(yī)科大學(xué);2014年

5 張鷗;阿托伐他汀對動脈粥樣硬化患者外周血中PPAR γ的作用研究及相關(guān)炎癥因子與動脈粥樣硬化關(guān)系的建模分析[D];鄭州大學(xué);2016年

6 周毅;PPARγ介導(dǎo)的抗氧化機制在血管平滑肌細胞表型轉(zhuǎn)化中作用和機制研究[D];第三軍醫(yī)大學(xué);2016年

7 滕志朋;PPARβ/δ在大鼠蛛網(wǎng)膜下腔出血后早期腦損傷中的作用及其機制研究[D];重慶醫(yī)科大學(xué);2016年

8 佟強;PPARβ/δ激活在帕金森病中的保護作用及機制研究[D];南京醫(yī)科大學(xué);2016年

9 張花治;紅芪多糖對db/db小鼠糖尿病心肌病心肌保護作用及PPARγ/NF-κB信號通路的影響[D];甘肅中醫(yī)藥大學(xué);2017年

10 任凌云;T細胞PPARγ在心臟移植慢性排反應(yīng)中的作用及機制研究[D];華中科技大學(xué);2016年

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1 曹智麗;過氧化物酶增殖物激活受體α（PPARα）在大鼠酒精性肝病發(fā)生過程中的變化[D];河北醫(yī)科大學(xué);2015年

2 宋石;miR-27a通過靶向調(diào)控PPARγ對酒精誘導(dǎo)大鼠BMSC分化的影響[D];鄭州大學(xué);2015年

3 鄒佳楠;PPAR-γ在IgA腎病發(fā)生中的作用及其機理研究[D];復(fù)旦大學(xué);2014年

4 陶曉燕;PPAR δ激動劑和siRNA對大鼠骨髓基質(zhì)干細胞及成骨細胞分化和礦化的作用研究[D];安徽醫(yī)科大學(xué);2015年

5 于飛;新型PPARγ激動劑對人腎癌細胞增殖抑制及其機制的研究[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2015年

6 何修界;PPARγ激活對GDM小鼠胎盤脂肪酸運輸?shù)鞍妆磉_水平的影響[D];安徽醫(yī)科大學(xué);2015年

7 魏璇;PPARγ通過對RUVBL2表達調(diào)控影響脂聯(lián)素分泌的研究[D];華中農(nóng)業(yè)大學(xué);2015年

8 游潔冰;PPARγ激動劑、胰島素通過上調(diào)負性炎性因子TIPE2的表達抑制高糖、Aβ1-40引起的炎性反應(yīng)及神經(jīng)細胞調(diào)亡[D];山東大學(xué);2015年

9 劉常為;CTGF、COL-I、PPARγ在卵巢細胞外基質(zhì)的表達及與多囊卵巢綜合征的關(guān)系[D];暨南大學(xué);2015年

10 曹小潔;TLR4通過PPARγ下調(diào)ABCG1表達促進血管平滑肌細胞內(nèi)炎癥反應(yīng)及脂質(zhì)沉積[D];第三軍醫(yī)大學(xué);2015年

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