本文關(guān)鍵詞：基于菊苣菊粉調(diào)節(jié)JNK和p38 MAPK信號(hào)通路對(duì)Ⅱ型糖尿病血糖作用機(jī)制的研究　出處：《沈陽(yáng)農(nóng)業(yè)大學(xué)》2017年博士論文　論文類(lèi)型：學(xué)位論文

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【摘要】：菊苣菊粉(Chicory inulin,CI)是一種水溶性食物纖維,不能被人體消化,也是一種天然存在的多聚果糖,這種多聚果糖具有降血糖、降血脂以及提高免疫力等作用。以往的研究表明,菊苣菊粉能夠促進(jìn)胰島分泌胰島素,并通過(guò)影響糖代謝酶的活性抑制糖異生,從而產(chǎn)生降血糖的作用,但其干預(yù)Ⅱ型糖尿病的具體作用機(jī)制尚未完全闡明,因此本研究通過(guò)對(duì)Ⅱ型糖尿病模型大鼠口服菊苣菊粉,探討其對(duì)Ⅱ型糖尿病模型大鼠的血糖、體重及糖脂代謝的影響,并通過(guò)體內(nèi)和體外試驗(yàn)探究菊苣菊粉通過(guò)調(diào)節(jié)JNK和p38 MAPK信號(hào)通路對(duì)Ⅱ型糖尿病大鼠血糖的改善作用,揭示菊苣菊粉對(duì)Ⅱ型糖尿病大鼠降血糖作用的機(jī)制,為應(yīng)用菊苣菊粉適合Ⅱ型糖尿病人群的食品開(kāi)發(fā)提供相關(guān)的理論依據(jù)。本論文具體主要研究?jī)?nèi)容及結(jié)論如下:腹腔注射45 mg/kg鏈脲佐菌素(Streptozotocin,STZ),結(jié)合高脂飲食喂養(yǎng)構(gòu)建T2DM大鼠模型,正常對(duì)照組大鼠靜脈注射等體積生理鹽水,常規(guī)飼料喂養(yǎng)。造模成功后隨機(jī)分為6組:正常對(duì)照組(Control組)、模型組(T2DM組)、菊苣菊粉低劑量組(2.5g/kg CI組)、菊苣菊粉中劑量組(5g/kgCI組)、菊苣菊粉高劑量組(10g/kgCI組)、二甲雙胍對(duì)照組(Metformin組)。連續(xù)灌胃給藥8周,除正常對(duì)照組,剩余組大鼠采用高脂飲食喂養(yǎng)。8周給藥期結(jié)束后,檢測(cè)各組大鼠血糖濃度,測(cè)量記錄大鼠體重。結(jié)果顯示,與正常組大鼠相比,Ⅱ型糖尿病模型大鼠血糖濃度顯著升高(p0.01),且Ⅱ型糖尿病模型大鼠體重均小于正常組大鼠(p0.01);說(shuō)明菊苣菊粉可以降低Ⅱ型糖尿病模型大鼠血糖濃度,同時(shí)有效增加Ⅱ型糖尿病模型大鼠體重。研究菊苣菊粉對(duì)Ⅱ型糖尿病大鼠血脂代謝能力的影響,檢測(cè)各組大鼠血紅蛋白(Hemoglobin,HB)、糖化血紅蛋白(Hemoglobin A1c,HbA1c)、胰島素(Insulin,INS)、甘油三酯(Triglyceride,TG)、總膽固醇(Total cholesterol,TC)、游離脂肪酸(Nonesterified fatty acid,NEFA)等血脂代謝指標(biāo)含量。結(jié)果顯示,Ⅱ型糖尿病模型大鼠高脂喂養(yǎng)8周后血清中HB、HbA1c、INS、TG、TC、NEFA含量均顯著性上升(p0.05),給藥8周后,藥物干預(yù)組HB、HbA1c、INS、TG、TC、NEFA含量均表現(xiàn)不同程度下降。說(shuō)明菊苣菊粉能夠改善Ⅱ型糖尿病大鼠血脂代謝紊亂。為了闡明菊苣菊粉改善糖尿病的分子機(jī)制,本研究通過(guò)Western blot法檢測(cè)與糖脂代謝有關(guān)的JNK和p38 MAPK信號(hào)通路相關(guān)蛋白IRS、JNK及p38在肝臟和肌肉組織中的活化情況。結(jié)果顯示,菊苣菊粉可以有效活化骨骼肌和肝臟組織中IRS信號(hào),抑制JNK和p38 MAPK信號(hào)通路,并且菊苣菊粉這種干預(yù)作用具有一定的濃度依賴(lài)性。為進(jìn)一步驗(yàn)證菊苣菊粉可以在體外通過(guò)調(diào)節(jié)JNK和p38 MAPK通路改善Ⅱ型糖尿病大鼠的血糖,采用MTT法檢測(cè)不同濃度菊苣菊粉對(duì)小鼠成肌細(xì)胞C2Cl2和人肝癌細(xì)胞HepG2生長(zhǎng)活性的影響,結(jié)果顯示,在0～2.0mg/mL范圍內(nèi),菊苣菊粉對(duì)C2C12和HepG2細(xì)胞生長(zhǎng)均無(wú)顯著性影響。通過(guò)熒光標(biāo)記葡萄糖類(lèi)似物法檢測(cè)菊苣菊粉對(duì)C2C12和HepG2葡萄糖攝取能力的影響。結(jié)果顯示,隨著菊苣菊粉濃度的升高,C2C12和HepG2葡萄糖攝取能力也隨之增強(qiáng)。同時(shí)Western blot結(jié)果顯示,菊苣菊粉在體外亦能通過(guò)下調(diào)C2C12和HepG2細(xì)胞的JNK和p38 MAPK信號(hào)活性發(fā)揮作用。此外,為了進(jìn)一步闡明JNK和p38 MAPK信號(hào)與菊苣菊粉在調(diào)控葡萄糖代謝中的作用,通過(guò)分別使用JNK信號(hào)抑制劑SP600125和p38 MAPK信號(hào)抑制劑SB203580處理,采用熒光標(biāo)記葡萄糖類(lèi)似物法檢測(cè)細(xì)胞糖攝取能力的變化,結(jié)果顯示,抑制JNK和p38 MAPK信號(hào)時(shí)可協(xié)同菊苣菊粉進(jìn)一步增強(qiáng)細(xì)胞葡萄糖攝取能力。以上試驗(yàn)結(jié)果說(shuō)明,菊苣菊粉可以降低Ⅱ型糖尿病模型大鼠的血糖、HB、HbA1c、INS、TG、TC、NEFA的濃度,改善Ⅱ型糖尿病大鼠血脂代謝功能,并有效增加Ⅱ型糖尿病模型大鼠的體重;同時(shí)菊苣菊粉能有效活化IRS信號(hào),并通過(guò)抑制JNK和p38 MAPK信號(hào)通路增強(qiáng)細(xì)胞葡萄糖攝取能力,進(jìn)而對(duì)Ⅱ型糖尿病大鼠的血糖起到改善作用。
[Abstract]:Chicory inulin (Chicory inulin CI) is a kind of water soluble dietary fiber can not be digested, but also polyfructose a natural existence, the polyfructose has hypoglycemic, hypolipidemic and improving immune function. Previous studies showed that chicory inulin can promote islet insulin secretion, and the effect of sugar metabolism enzyme activity inhibition of gluconeogenesis, resulting in hypoglycemic effect, but its specific mechanism of intervention of type II diabetes has not been fully elucidated, so this study of type II diabetes rat model of oral chicory inulin, explore the type II diabetic rats blood glucose, weight and lipid metabolism and, in vivo and in vitro study of chicory inulin by regulating the effects of JNK and p38 of MAPK signaling pathway on blood glucose in type II diabetic rats, to reveal the chicory inulin type II diabetes hypoglycemic rats The mechanism, to provide a theoretical basis for the development of food related application of chicory inulin for people with type 2 diabetes. In this paper the main research contents and conclusions are as follows: 45 mg/kg intraperitoneal injection of streptozotocin (Streptozotocin, STZ), to construct T2DM rat model with high fat diet, the rats in the normal control group vein injection of saline, conventional diet. The rats were randomly divided into 6 groups: normal control group (Control group), model group (T2DM group), low dose group of chicory inulin (2.5g/kg CI group), dose group of chicory inulin (5g/kgCI group), chicory inulin in high dose group (10g/kgCI group metformin), control group (group Metformin). Continuous gavage for 8 weeks, in addition to the normal control group, the remaining rats with high fat diet.8 weeks after the end of the period, the detection of blood glucose concentration in rats, measured body weights were recorded. The results showed that with the normal group Compared with rats, blood glucose concentration in rats model of type II diabetes significantly increased (P0.01), and the weight of type II diabetic rats were lower than normal rats (P0.01); that of chicory inulin can reduce the concentration of blood glucose in type II diabetic rat model, and effectively increase the body weight of model rats of type II diabetes sugar. Study of chicory inulin on lipid metabolism ability of type II diabetic rats, hemoglobin of rats (Hemoglobin, HB), glycosylated hemoglobin (Hemoglobin A1c, HbA1c), insulin (Insulin, INS), triglycerides (Triglyceride, TG), total cholesterol (Total, cholesterol, TC), free fatty acids (Nonesterified fatty acid NEFA, etc.) the blood lipid content. The results showed that high fat diet in type II diabetic rats after 8 weeks, serum HB, HbA1c, INS, TG, TC, NEFA were significantly increased (P0.05), 8 weeks after drug administration, drug intervention group HB, HbA1c, INS, TG, TC, NEFA content were decreased in different degrees. It can improve the chicory inulin dyslipidemia in type II diabetic rats. To elucidate the molecular mechanism of chicory inulin improve diabetes, the study by the Western blot method to detect the JNK and p38 with glucose and lipid metabolism of MAPK signaling pathway related proteins IRS, JNK and p38 activation in the liver and in the muscle tissue. The results showed that chicory inulin can effectively activate IRS signaling in skeletal muscle and liver tissue, inhibition of JNK and p38 MAPK signaling pathway, and the effect of this intervention with chicory inulin in a concentration dependent manner. In order to further verify the chicory inulin in vitro by regulating JNK and p38 MAPK pathway to improve type the blood sugar, effects of different concentrations of chicory inulin on detection of mouse myoblasts and C2Cl2 human hepatocarcinoma cell line HepG2 activity by MTT method. The results show that in 0 ~ 2. The range of 0mg/mL, chicory inulin had no significant effect on C2C12 and HepG2 cell growth. Detected by fluorescent labeling of chicory inulin glucose analogs of C2C12 and HepG2 glucose uptake. The results showed that with increasing concentration of C2C12 and HepG2 of chicory inulin, glucose uptake is enhanced. At the same time, Western blot showed that can also play the role of chicory inulin, by JNK and p38 MAPK signaling down-regulation of C2C12 and HepG2 cells in vitro. In addition, in order to further clarify the JNK and the p38 MAPK signal in the regulation of glucose metabolism and chicory inulin in effect, by respectively using JNK and p38 MAPK signal pathway inhibitor SP600125 SB203580 inhibitor, change by fluorescence the glucose analogue method to detect cell glucose uptake ability showed that inhibition of JNK and p38 MAPK signal can further enhance the synergy of Chicory Inulin Cell glucose uptake. These results indicate that the chicory inulin can reduce type II diabetic rats blood glucose, HB, HbA1c, INS, TG, TC, NEFA concentration, improve blood lipid metabolism in type II diabetic rats, and effectively increase the type II diabetic rats weight; chicory inulin can effectively at the same time activation of IRS signaling, and enhanced cellular glucose uptake through inhibition of JNK and p38 MAPK signaling pathway, then the type II diabetic rats blood sugar to improve.

【學(xué)位授予單位】：沈陽(yáng)農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：TS201.4

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本文編號(hào)：1391111