本文選題：胰島素抵抗 + microRNA�。� 參考：《北京中醫(yī)藥大學(xué)》2017年博士論文

【摘要】：目的:探討輔助降糖顆粒與二甲雙胍聯(lián)合用藥對(duì)ZDF大鼠胰島素抵抗的作用及機(jī)制,為中西藥聯(lián)合應(yīng)用提供科學(xué)依據(jù),為臨床用藥提供指導(dǎo)。方法:采用隨機(jī)對(duì)照設(shè)計(jì)方法,動(dòng)物實(shí)驗(yàn)選取自發(fā)性2型糖尿病動(dòng)物模型ZDF(fa/fa)大鼠28只,pumina#5008飼料誘導(dǎo)性喂養(yǎng)4周,不同次隨機(jī)血糖≥11.1 mmol/L納入實(shí)驗(yàn)。按體重、隨機(jī)血糖隨機(jī)分為:模型組、二甲雙胍組、輔助降糖顆粒組(降糖顆粒組)、輔助降糖顆粒聯(lián)合二甲雙胍組(聯(lián)合組),每組7只;另設(shè)7只同周齡正常ZDF(fa/+)大鼠為正常組,連續(xù)干預(yù)6周。實(shí)驗(yàn)過程中觀察記錄大鼠一般情況、體重、空腹血糖,第6周分別進(jìn)行OGTT、ITT實(shí)驗(yàn);6周后大鼠麻醉、取血,分別凍存和固定肝臟,檢測血清中IR相關(guān)指標(biāo)FBG、Fins和HOMA-IR,血脂指標(biāo)TG、TC和FFA,肝腎功能指標(biāo)AST、Scr和BUN,氧化應(yīng)激和炎性細(xì)胞因子MDA、SOD、CAT和TNF-α,以及細(xì)胞因子Adiponectin、Resistin;檢測肝臟糖原含量,行HE、PAS染色觀察肝臟病理形態(tài)變化;高通量測序檢測肝臟microRNAs表達(dá),NCBI、The Gene ontology、KEGG、TIGR、miRBase數(shù)據(jù)庫對(duì)差異microRNAs進(jìn)行生物信息學(xué)分析,預(yù)測靶通路;Western blot 檢測 IRS1ser307/ser612/ser1101/Tyr989、PI3K、Akt、GSK-3β 磷酸化水平以及 Real time-PCR檢測肝臟InsR、G-6-P、PEPCKmRNA表達(dá),來驗(yàn)證microRNAs生物信息學(xué)分析結(jié)果。細(xì)胞實(shí)驗(yàn)采用雄性SD大鼠50只,適應(yīng)性喂養(yǎng)1周,按體重隨機(jī)分為:正常組、二甲雙胍組、輔助降糖顆粒組(降糖顆粒組)、輔助降糖顆粒聯(lián)合二甲雙胍組(聯(lián)合組),每組10只,每日早晚各給藥1次,連續(xù)給藥7次后麻醉取血獲得含藥血清。H4IIE肝細(xì)胞常規(guī)復(fù)蘇、培養(yǎng),胰島素濃度為10-6mol/L的培養(yǎng)基誘導(dǎo)36 h建立肝細(xì)胞胰島素抵抗模型,含藥血清進(jìn)行干預(yù)后,CCK-8法檢測細(xì)胞活性;Westernblot和Real time-PCR檢測胰島素信號(hào)通路關(guān)鍵靶點(diǎn)基因、蛋白表達(dá),驗(yàn)證動(dòng)物實(shí)驗(yàn)結(jié)果。結(jié)果:1.血清學(xué)檢測:①在改善IR和糖脂代謝方面,與正常組大鼠比較,模型組大鼠血清FBG、Fins和HOMA-IR明顯升高(P0.01或P0.05),OGTT、ITT試驗(yàn)峰值延后(P0.01或P0.05),體重、肝重、肝重/體重以及TG、TC和FFA顯著升高(P0.01或P0.05),而肝糖原含量顯著降低(P0.01);與模型組比較,聯(lián)合組顯著降低大鼠FBG、Fins、HOMA-IR、體重、肝重、肝重/體重以及TG、TC和FFA(P0.01或P0.05),顯著升高肝糖原含量(P0.01),而且效果優(yōu)于二甲雙胍組和降糖顆粒組(P0.01或P0.05)。②在改善氧化應(yīng)激和細(xì)胞因子方面,與正常組大鼠比較,模型組大鼠血清 MDA、Resistin、TNF-α 顯著升高(P0.01 或 P0.05),而 SOD、CAT、Adiponectin 水平顯著降低(P0.01 或 P0.05);聯(lián)合組大鼠血清 MDA、Resistin、TNF-a顯著降低(P0.01 或P0.05),SOD、CAT、Adiponectin 水平顯著升高(P0.01 或 P0.05),其中調(diào)節(jié)MDA、SOD、CAT、Adiponectin、TNF-α的效果優(yōu)于二甲雙胍組、降糖顆粒組(P0.01或P0.05)。③在肝腎功能方面,各組間AST無差異;模型組Scr、BUN較正常組顯著升高(P0.01),而二甲雙胍組、降糖顆粒組、聯(lián)合組較模型組顯著降低(P0.01),聯(lián)合組與二甲雙胍組比較Scr顯著降低(P0.05)。2.形態(tài)學(xué)檢測:HE染色顯示各藥物干預(yù)組肝細(xì)胞較模型組排列整齊、脂肪樣變性減輕、炎細(xì)胞浸潤減少;PAS染色顯示各藥物干預(yù)組較模型組胞質(zhì)中紫紅色糖原顆粒分布增多,聯(lián)合組更為明顯。3.microRNAs生物信息學(xué)分析:藥物干預(yù)6周后,進(jìn)行大鼠肝臟microRNA測序及差異基因趨勢分析發(fā)現(xiàn),與正常組、模型組比較,二甲雙胍組rno-miR-182、rno-miR-33-3p、rno-miR-33-5p、rno-miR-3553、rno-miR-96-5p發(fā)生差異性趨勢變化,降糖顆粒組rno-miR-122-3p、rno-miR-33-3p、rno-miR-33-5p、rno-miR-22-3p 發(fā)生差異性趨勢變化,聯(lián)合組 rno-miR-122-3p、rno-miR-33-3p、rno-miR-33-5p、rno-miR-742-3p、rno-miR-22-3p發(fā)生差異性趨勢變化(P0.01或P0.05);對(duì)差異趨勢顯著的microRNA進(jìn)一步行靶基因預(yù)測、功能分析以及Pathway分析顯示,與正常組、模型組比較,二甲雙胍組、降糖顆粒組、聯(lián)合組均顯著性影響胰島素信號(hào)傳導(dǎo)通路,但聯(lián)合組顯著性較二甲雙胍組、降糖顆粒組更強(qiáng)。4.Western blot和Real time-PCR檢測:與模型組比較,聯(lián)合組大鼠肝臟IRS1ser307/ser612/ser1101 蛋白磷酸化水平顯著降低(P0.01 或 P0.05),IRS1Tyr989、PI3K、Akt、GSK-3β蛋白磷酸化水平顯著升高(P0.01或P0.05),InsRmRNA表達(dá)顯著升高(P0.01),G-6-P、PEPCKmRNA表達(dá)顯著降低(P0.01);而與二甲雙胍組、降糖顆粒組比較,聯(lián)合組調(diào)控以上蛋白和基因表達(dá)的效果顯著,存在差異性(P0.01 或 P0.05)。5.肝細(xì)胞檢測結(jié)果:對(duì)胰島素抵抗肝細(xì)胞活性檢測顯示,模型組含藥血清干預(yù)后細(xì)胞活性較正常組顯著降低(P0.01);二甲雙胍組、降糖顆粒組、聯(lián)合組較模型組顯著升高(P0.01);聯(lián)合組較二甲雙胍組、降糖顆粒組顯著升高(P0.01或P0.05)。Western blot和Real time-PCR檢測顯示,聯(lián)合組含藥血清干預(yù)后細(xì)胞較模型組IRS1ser307/ser612/ser1101蛋白磷酸化水平顯著降低(P0.01 或 P0.05),IRS1Tyr989、PI3K、Akt、GSK-3β蛋白磷酸化水平顯著升高(P0.01或P0.05),InsRmRNA表達(dá)顯著升高(P0.01),G-6-P、PEPCK mRNA表達(dá)顯著降低(P0.01);而與二甲雙胍組、降糖顆粒組比較,聯(lián)合組調(diào)控以上蛋白和基因表達(dá)的效果顯著,存在差異性(P0.01 或 P0.05)。結(jié)論:輔助降糖顆粒聯(lián)合二甲雙胍明顯改善糖尿病大鼠IR以及糖脂代謝紊亂,促進(jìn)糖原合成,效果優(yōu)于二甲雙胍、輔助降糖顆粒單獨(dú)應(yīng)用,其機(jī)制可能是通過調(diào)節(jié)microRNA差異表達(dá),來調(diào)控胰島素信號(hào)傳導(dǎo)通路中IRS1、PI3K、Akt、GSK-3磷酸化及InsR、G-6-P、PEPCK基因表達(dá),發(fā)揮改善IR的作用;此外,輔助降糖顆粒聯(lián)合二甲雙胍還具有抗氧化,調(diào)節(jié)細(xì)胞因子Adiponectin、Resistin、TNF-α的作用,這可能也是其作用機(jī)制之一。
[Abstract]:Objective: To explore the effect and mechanism of the combination of auxiliary hypoglycemic granule and metformin on insulin resistance in ZDF rats, provide scientific basis for the combination of Chinese and Western medicine and provide guidance for clinical use. Methods: a randomized controlled design method was used and 28 fa/fa rats of spontaneous type 2 diabetes were selected and 28 rats were selected, pumina#5008 Feed inducible feeding for 4 weeks, different random blood glucose more than 11.1 mmol/L were included in the experiment. According to weight, random blood sugar was randomly divided into model group, metformin group, auxiliary hypoglycemic group (hypoglycemic granule group), auxiliary hypoglycemic granule combined with metformin group (combined group), 7 rats in each group, and 7 normal ZDF (fa/+) rats of the same week age as the normal group, continuous dry During the 6 weeks, the general condition, body weight, fasting blood glucose, OGTT, ITT experiment were recorded in sixth weeks. After 6 weeks, rats were anesthetized, and blood was taken to freeze and fix the liver respectively. The serum IR related indexes, FBG, Fins and HOMA-IR, TG, TC and FFA, liver and kidney function indicators AST, Scr and BUN, oxidative stress and inflammatory cell cause were detected. MDA, SOD, CAT and TNF- alpha, as well as cytokines Adiponectin, Resistin; detection of liver glycogen content, HE, PAS staining to observe the liver pathological changes; high throughput sequencing detection of liver microRNAs expression, NCBI, The Gene. T test IRS1ser307/ser612/ser1101/Tyr989, PI3K, Akt, GSK-3 beta phosphorylation level and Real time-PCR to detect liver InsR, G-6-P, PEPCKmRNA expression to verify the results of microRNAs bioinformatics analysis. Cell experiments used 50 male SD rats for 1 weeks, and were randomly divided into normal group, metformin group and auxiliary hypoglycemic group according to body weight. Granule group (Jiangtang granule group), auxiliary hypoglycemic granule combined with metformin group (combined group), 10 rats in each group were given 1 times a day and morning and evening. After 7 times of continuous administration, blood was taken to obtain serum.H4IIE liver cell routine resuscitation and culture. The insulin concentration was induced by 10-6mol/L in 36 h to establish the liver cell insulin resistance model. The cell activity was detected by CCK-8 method, and the key target genes of insulin signaling pathway were detected by Westernblot and Real time-PCR, and the protein expression was detected. Results: 1. serological test: 1. In improving IR and glycolipid metabolism, the serum FBG, Fins and HOMA-IR in the model group were significantly higher than those in the normal group (P0.01). Or P0.05), OGTT, ITT test peak delay (P0.01 or P0.05), weight, liver weight, liver weight / weight and TG, TC and FFA significantly increased (P0.01 or P0.05), while liver glycogen content decreased significantly (P0.01). Compared with the model group, the combined group significantly reduced the rats' FBG, weight, liver weight, liver weight / weight, and significantly increased Liver glycogen content (P0.01), and the effect is better than metformin group and hypoglycemic group (P0.01 or P0.05). (2) in improving oxidative stress and cytokines, compared with normal rats, the serum MDA, Resistin, TNF- alpha in the model group increased significantly (P0.01 or P0.05), but SOD, CAT, Adiponectin level decreased significantly (P0.01 or P0.05). The serum MDA, Resistin, and TNF-a decreased significantly (P0.01 or P0.05), SOD, CAT, Adiponectin level increased significantly (P0.01 or P0.05). The effect of regulation MDA, SOD, and Adiponectin was better than that of metformin group and hypoglycemic granule group. Significantly increased (P0.01), and metformin group, hypoglycemic group, combined group was significantly lower than the model group (P0.01), the combination group and metformin group compared with the metformin group significantly lower (P0.05).2. morphological detection: HE staining showed that the liver cells in the drug intervention group were arranged in a whole group, the adipose degeneration and inflammatory cell infiltration decreased; PAS staining showed that each group was Scr. In the drug intervention group, the distribution of the purple red glycogen granules in the cytoplasm of the model group increased, and the combined group was more obviously.3.microRNAs bioinformatics analysis. After 6 weeks of drug intervention, the microRNA sequencing and differential gene trend analysis of rat liver were found, compared with the normal group, the model group, and the group of two metformin groups rno-miR-182, rno-miR-33-3p, rno-miR-33-5p, rno-. The difference trend of miR-3553, rno-miR-96-5p, rno-miR-122-3p, rno-miR-33-3p, rno-miR-33-5p, rno-miR-22-3p in the group of hypoglycemic granula was changed, and the trend changes of rno-miR-122-3p, rno-miR-33-3p, rno-miR-33-5p, rno-miR-742-3p, and rno-miR-22-3p in the combination group were different. IcroRNA further target gene prediction, functional analysis and Pathway analysis showed that compared with the normal group, the model group, the metformin group, the hypoglycemic granule group and the combined group significantly affected the insulin signaling pathway, but the combined group was significantly more.4.Western blot and Real time-PCR in the metformin group and the hypoglycemic granule group: and the model of the model. The level of phosphorylation of IRS1ser307/ser612/ser1101 protein in the liver of the combined group was significantly lower (P0.01 or P0.05), IRS1Tyr989, PI3K, Akt, the level of phosphorylation of GSK-3 beta protein was significantly increased (P0.01 or P0.05), InsRmRNA expression increased significantly (P0.01), G-6-P, and the expression of InsRmRNA was significantly lower than that in the metformin group, and the ratio of hypoglycemic granule group was compared with the group of metformin. Compared with the combination group, the effect of the above protein and gene expression was significant, and there was a difference (P0.01 or P0.05).5. hepatocyte detection results: the activity of insulin resistant liver cells showed that the cell activity of the model group was significantly lower than that of the normal group (P0.01) after the intervention of the drug serum, and the metformin group and the combination group were more significant than the model group. Higher (P0.01); compared with metformin group, the level of.Western blot and Real time-PCR in the group of hypoglycemic granule group (P0.01 or P0.05) showed that the level of IRS1ser307/ser612/ser1101 protein phosphorylation in the combined group was significantly lower than that of the model group (P0.01 or P0.05), IRS1Tyr989, PI3K, and beta protein phosphorylation level. Significantly increased (P0.01 or P0.05), InsRmRNA expression significantly increased (P0.01), G-6-P, PEPCK mRNA expression significantly decreased (P0.01), and compared with the metformin group, hypoglycemic group, the combined control of the protein and gene expression of the effect is significant, there is a difference (P0.01 or P0.05). Conclusion: auxiliary hypoglycemic Granules Combined with metformin obviously improved sugar. Urinary disease rats IR and glycolipid metabolic disorders, promote glycogen synthesis, the effect is better than metformin, the effect is better than metformin, auxiliary hypoglycemic granules alone, the mechanism may be by regulating the differential expression of microRNA, to regulate the insulin signal transduction pathway IRS1, PI3K, Akt, GSK-3 phosphorylation and InsR, G-6-P, PEPCK gene expression, play the role of improving IR; in addition, supplemented by the role of IR; in addition, auxiliary The combination of "Jiangtang Granule" and metformin also has antioxidant effect, which regulates cytokine Adiponectin, Resistin and TNF- alpha. This may be one of its mechanisms.
【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R965

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