本文選題：胰島素降解酶 + 胰島素抵抗　； 參考：《東南大學》2017年博士論文

【摘要】：第一部分 IDE與胰島素抵抗和糖尿病MCI的相關性研究背景:胰島素降解酶(IDE)可降解胰島素和β-淀粉樣蛋白(Aβ),與2型糖尿病慢性并發(fā)癥及(AD)的發(fā)生發(fā)展有密切的關系。胰島素抵抗(IR)是2型糖尿病的始發(fā)因素之一,既往研究表明IR會增加認知功能障礙甚至AD的發(fā)生風險,也是糖尿病輕度認知障礙(MCI)向AD轉化的危險因素。目的:研究IDE與胰島素抵抗、2型糖尿病MCI的相關關系,探討IDE對2型糖尿病MCI發(fā)生的預測價值。方法:本研究共招募239位2型糖尿病患者,根據(jù)MoCA得分將其分為MCI組和認知功能正常組。所有受試者入組后于次日早晨7點空腹抽取靜脈血,測定空腹血糖、空腹C肽、糖化血紅蛋白、肝腎功能、血脂全套,計算胰島素抵抗指數(shù)(HOMA-IR)。用多維度量表評估受試者的認知功能,用聚合酶鏈式反應-限制性片段長度多態(tài)性法檢測IDE rs4646958基因多態(tài)性,并用酶聯(lián)免疫吸附法測定血清IDE濃度。結果:納入的2型糖尿病患者中,132人符合MCI的診斷標準,107人是與之相匹配的認知功能正常組。結果表明:1、與認知功能正常組比較,2型糖尿病MCI組患者的血清IDE顯著降低(P0.001),HOMA-IR顯著升高(P0.001); 2、在2型糖尿病MCI患者中,血清IDE水平和MoCA得分呈顯著正相關(r = 0.827;P0.001 ),HOMA-IR和MoCA得分呈顯著負相關(r = -0.644;P0.001); 3、在所有2型糖尿病患者中做的相關分析表明,血清 IDE 水平和 MoCA 得分(r = 0.798;P 0.001)呈正相關,和 HOMA-IR (r =-0.586;P 0.001 )、連線試驗 A (r =-0.464;P 0.001 )、連線試驗 B (r = -0.399;P 0.001)、空腹血糖(r = -0.409;P0.001)、糖化血紅蛋白(r = -0.237;P= 0.015)及平均血糖波動幅度(r =-0.502;P 0.001)呈負相關;4、回歸分析顯示,調整了年齡、性別、受教育年限、肝腎功能和血脂水平后,IDE(P=0.001)、糖化血紅蛋白(P=0.024)、空腹C肽(P0.001)是2型糖尿病發(fā)生MCI的影響因素;5、IDE rs4646958基因型在2型糖尿病認知障礙組及認知功能正常組均未發(fā)現(xiàn)統(tǒng)計學差異。結論:IDE參與胰島素抵抗相關的2型糖尿病早期認知功能障礙(特別是執(zhí)行功能),可能成為早期的預測指標。IDE rs4646958基因多態(tài)性在2型糖尿病認知障礙中并未發(fā)現(xiàn)顯著統(tǒng)計學結果,需要大規(guī)模樣本進一步明確其在易感人群中的預測價值。第二部分 IDE參與KKAy小鼠認知功能障礙的機制及PPARy激動劑的干預效應背景:胰島素抵抗是2型糖尿病的最顯著的臨床病理特征,早于顯著的2型糖尿病癥狀發(fā)生,參與了糖尿病早期認知障礙的發(fā)生以及向AD的轉化。過氧化物酶增殖物活化受體γ(PPARγ)的表達和胰島素的敏感性呈正相關,它可以通過調節(jié)胰島素信號通路,調控IDE的表達。PPARy激動劑可改善胰島素抵,減少認知功能障礙和AD的發(fā)生。我們前期的研究發(fā)現(xiàn)2型糖尿病MCI的患者中,血清IDE水平較低,和胰島素抵抗介導的認知功能下降顯著相關,可能是2型糖尿病發(fā)生認知障礙的預測指標。在臨床研究的基礎上,我們進一步通過動物實驗來證實IDE參與胰島素抵抗相關的認知障礙機制和PPARy激動劑的預防和干預效應。目的:從動物水平上探討IDE保護動物認知功能的可能機制及其與Aβ水平的相關性,以及PPARγ激動劑在胰島素抵抗介導的2型糖尿病小鼠認知功能損傷的預防和治療效果。方法:本研究采用高脂喂養(yǎng)KKAy小鼠作為2型糖尿病輕度認知功能障礙模型,羅格列酮作為PPARy激動劑對小鼠進行預防和干預。選取6周齡清潔級健康雄性KKAy小鼠和其對應的C57BL/6j (C57)小鼠(均購于中國醫(yī)學科學院實驗動物所),適應性喂養(yǎng)一周。其中隨機選出三組KKAy小鼠在8周齡時分別給予低、中、高劑量羅格列酮預防,其他三組在小鼠15周齡出現(xiàn)認知障礙時給予羅格列酮低、中、高劑量干預,還有一組作為2型糖尿病未干預的對照組。將羅格列酮溶于0.9%生理鹽水中配置成所需濃度的混懸液,低劑量組每天予1mg/ (kg·d)灌胃,中劑量組每天予3.3mg/ (kg d)灌胃,高劑量組每天予10mg/ (kg· d)灌胃,糖尿病對照組及正常組C57小鼠予等劑量生理鹽水灌胃3個月。處理后進行以下檢測:1、每周監(jiān)測小鼠體質量、空腹血糖及空腹胰島素水平,計算出相關的胰島素抵抗指數(shù);2、通過水迷宮及避暗實驗觀察小鼠的行為學變化;3、Western及RT-PCR法測定小鼠海馬PPARγ、IDE的mRNA及蛋白水平;4、對腦組織切片進行HE染色、尼氏染色,鏡下觀察各組小鼠大腦組織神經(jīng)元形態(tài)、尼氏體的改變;5、免疫化學法測定小鼠腦組織PPARγ、IDE、Aβ的表達。結果:1、各組小鼠體質量、空腹血糖、胰島素和胰島素抵抗指數(shù)水平的比較:各周齡KKAy小鼠的體質量、空腹血糖、胰島素及胰島素抵抗水平均高于對照組C57小鼠(P 0.05),和模型對照組相比,羅格列酮預防和干預組的體質量均無顯著統(tǒng)計學差異(P0.05),空腹血糖、胰島素及胰島素抵抗水平顯著下降(P0.05),高劑量效果更為顯著。2、各組小鼠行為學比較:水迷宮實驗結果表明,與正常對照組相比,模型對照組小鼠逃避潛伏期顯著延長,穿臺次數(shù)顯著減少(P0.05);與模型對照組小鼠相比,羅格列酮干預和預防組小鼠逃避潛伏期顯著減少,穿臺次數(shù)顯著延長(P0.05)。避暗實驗結果表明,和正常對照組小鼠相比,模型組小鼠避暗潛伏期顯著縮短,錯誤次數(shù)顯著增加(P0.05),羅格列酮低預防和干預后,潛伏期和錯誤次數(shù)均有顯著改善(P0.05),高劑量的效果尤其顯著。3、海馬組織PPARγ及IDE的mRNA及蛋白水平:模型對照組小鼠海馬內PPARy及IDE的mRNA及蛋白水平顯著下降(P0.05),經(jīng)羅格列酮預防和干預后PPARy及IDE的mRNA及蛋白水平均顯著增加(P 0.05),高劑量的效果尤其顯著。4、各組小鼠神經(jīng)元形態(tài)的改變:HE染色:正常對照組小鼠海馬組織中,神經(jīng)元細胞形態(tài)結構未見顯著異常,細胞核形狀呈圓形,細胞結構層次清楚且排列整齊。模型對照組小鼠海馬組織的部分細胞出現(xiàn)形態(tài)結構的破壞,細胞核皺縮,邊緣模糊,細胞結構排列松散,有變形甚至壞死。羅格列酮預防和干預后,小鼠海馬組織的細胞形態(tài)結構的破壞程度有所減輕,排列松散情況好轉,神經(jīng)元的變性壞死程度減輕,病理損傷有所好轉。尼氏染色:正常對照組小鼠海馬神經(jīng)元未見顯著異常,胞核膜和核仁較清楚;模型對照組小鼠的海馬、額葉皮質的細胞排列疏散、細胞間隙較寬,胞漿內Nissl體較少。羅格列酮預防和干預組小鼠與模型組小鼠比較,組織結構有所改善,神經(jīng)元細胞排列密集、整齊,胞漿中Nissl體增加。5、免疫化學法測定小鼠腦組織PPARγ、IDE、Aβ的表達:正常組小鼠海馬組織細胞排列緊密,胞體小,Aβ蛋白著色較淺,表達較弱。模型對照組小鼠海馬組織細胞排列疏松,胞體較大,Aβ著色深,表達呈強陽性,PpAaγ及IDE的IOD值顯著減少(P0.05)。羅格列酮預防和干預組小鼠PPARy及IDE的IOD值顯著增加,Aβ蛋白顯著減少(P0.05)。結論:IDE參與胰島素抵抗所致的糖尿病早期認知障礙,對認知功能起到保護作用。PPARγ激動劑可能是通過升高IDE和降低Aβ水平來預防和改善KKAy小鼠的認知功能障礙的。第三部分 IDE介導的PPARy激動劑對PC12細胞APP和Aβ的影響背景:前期實驗證實PPARγ激動劑可能是通過升高IDE和降低Aβ水平來預防和改善KKAy小鼠的認知功能障礙的。但在細胞水平,PPARy激動劑對神經(jīng)細胞的保護作用機制尚未明確。目的:研究IDE介導的PPARγ激動劑對PC12細胞淀粉樣前體蛋白(APP)和Aβ的影響,探討PPARy激動劑神經(jīng)保護作用可能的潛在機制。方法:選取未分化的PC12細胞株,以神經(jīng)生長因子誘導為神經(jīng)元細胞。預試驗采用1Oμmol/L的羅格列酮、20μmol/L的氯喹、12.5μmol/L的T0070907分別處理后,處理組和對照組相比具有顯著的統(tǒng)計學差異,后續(xù)的實驗就用該濃度作為理想濃度來處理PC12細胞。在細胞穩(wěn)定生長24小時后隨機分為六組:正常對照組、羅格列酮干預組、T0070907處理組、T0070907預處理+羅格列酮組、氯喹處理組、氯喹預處理+羅格列酮組,每個組設6個平行復孔。干預處理后收集各組相應時間點的細胞,用RT-PCR以及Western blotting分別檢測PPARγ、IDE、APP等指標mRNA和蛋白的表達水平;用ELISA法檢測細胞培養(yǎng)液上清液Aβ水平。結果:結果顯示:1、和正常對照組相比,羅格列酮干預組的PPARy和IDE的mRNA和蛋白含量顯著增加(P 0.05),APP的mRNA和蛋白含量顯著減少(P0.05); 2、單獨用T0070907處理組和用T0070907與羅格列酮聯(lián)合處理組相比,PPARγ、IDE和APP的mRNA和蛋白含量未見顯著統(tǒng)計學差異(P0.05); 3、和氯喹處理組相比,用氯喹與羅格列酮聯(lián)合處理組PPARy的mRNA和蛋白含量顯著升高,IDE和APP的mRNA和蛋白含量未見顯著統(tǒng)計學差異(P 0.05); 4、和正常對照組相比,羅格列酮干預組的PPARy和IDE的培養(yǎng)液上清液的Aβ含量顯著減少(P0.05),其他各組培養(yǎng)液上清液的Aβ含量未見顯著統(tǒng)計學差異(P0.05)。結論:PPARy激動劑可誘導DDE的表達,從而促進APP和Aβ的降解。但是,PPARy激動劑對IDE誘導的神經(jīng)細胞損傷的保護作用,均可被PPARy抑制劑T0070907及IDE抑制劑氯喹所拮抗,表明PPARγ激動劑的神經(jīng)細胞損傷的保護機制是通過PPARy激活IDE途徑參與調節(jié)的。
[Abstract]:The first part of the study on the correlation between IDE and insulin resistance and diabetes MCI: insulin degrading enzyme (IDE) degrading insulin and beta amyloid (A beta) is closely related to the development of chronic complications of type 2 diabetes and (AD). Insulin resistance (IR) is one of the initiation factors of type 2 diabetes. Previous studies have shown that IR will increase. The risk of cognitive dysfunction or even AD is also a risk factor for mild cognitive impairment of diabetes (MCI) to AD. Objective: To study the correlation between IDE and insulin resistance and MCI in type 2 diabetes, and to explore the predictive value of IDE for the occurrence of MCI in type 2 diabetes. Methods: a total of 239 patients with type 2 diabetes were recruited and the score of MoCA was based on the score of MoCA. It was divided into the MCI group and the normal cognitive function group. All the subjects took the venous blood at 7 a. m. on the next morning and measured the fasting blood glucose, fasting C peptide, glycosylated hemoglobin, liver and kidney function, blood lipid whole set, and calculated the insulin resistance index (HOMA-IR). The cognitive function of the subjects was evaluated by the multidimensional scale and the polymerase chain reaction restriction was used. The polymorphism of IDE rs4646958 gene was detected by sex fragment length polymorphism and serum IDE concentration was measured by ELISA. Results: among the patients with type 2 diabetes, 132 were in accordance with the diagnostic criteria of MCI and 107 were matched with the normal cognitive function group. The results showed that: 1, compared with the normal cognitive function group, the MCI group of type 2 diabetes mellitus was developed. Serum IDE was significantly decreased (P0.001) and HOMA-IR significantly increased (P0.001); 2, in type 2 diabetic MCI patients, serum IDE levels were positively correlated with MoCA scores (r = 0.827; P0.001), and HOMA-IR and MoCA scores were negatively correlated (r =;); 3, in all patients with type 2 diabetes, serum levels and levels MoCA score (r = 0.798; P 0.001) was positive correlation, and HOMA-IR (R =-0.586; P 0.001), connection test A (R =-0.464; P 0.001), connection test B (0.001), fasting blood glucose, glycated hemoglobin (0.015) and average blood glucose fluctuations (0.001) negative correlation; 4, regression analysis showed After adjusting age, sex, years of education, liver and kidney function and blood lipid levels, IDE (P=0.001), glycosylated hemoglobin (P=0.024), and fasting C peptide (P0.001) were the factors affecting MCI in type 2 diabetes; 5, IDE rs4646958 genotypes were not found in the cognitive impairment group of type 2 diabetes and the normal cognitive function group. Conclusion: IDE participates in the pancreas. The early cognitive impairment (especially executive function) of type 2 diabetes associated with Isle resistance may be an early predictor of the.IDE rs4646958 gene polymorphism in the cognitive impairment of type 2 diabetes, which requires a large sample to further clarify its predictive value in the susceptible population. Second part IDE The mechanism of participation in cognitive dysfunction in KKAy mice and the intervention effect of PPARy agonists: insulin resistance is the most significant clinicopathological feature of type 2 diabetes, earlier than the onset of type 2 diabetes, the occurrence of early cognitive impairment in diabetes and the conversion to AD. The peroxidase proliferator activated receptor gamma (PPAR gamma) ) expression is positively related to insulin sensitivity, and it can regulate the insulin signaling pathway by regulating the expression of IDE.PPARy agonists to improve insulin resistance and reduce the occurrence of cognitive dysfunction and AD. Our previous study found that in patients with type 2 diabetes MCI, the level of IDE in blood albumin was lower and the cognitive work mediated by insulin resistance was found in patients with type 2 diabetes. Reduced significant correlation, may be a predictor of cognitive impairment in type 2 diabetes. On the basis of clinical studies, we further confirmed the mechanism of cognitive impairment associated with insulin resistance and the prevention and intervention effects of PPARy agonists by IDE. Objective: To explore the cognitive function of IDE protection from animal levels. The possible mechanisms and their correlation with A beta levels, as well as the preventive and therapeutic effects of PPAR gamma agonists on cognitive impairment in type 2 diabetic mice induced by insulin resistance. Methods: This study used high fat feeding KKAy mice as a mild cognitive impairment model of type 2 diabetes, and rosiglitazone was used as a PPARy agonist to mice. Prevention and intervention. Select 6 week old clean healthy male KKAy mice and their corresponding C57BL/6j (C57) mice (all purchased in the laboratory animal Institute of Chinese Academy of Medical Sciences) for one week. Among them, three groups of KKAy mice were randomly selected to be given low, medium and high dose rosiglitazone at 8 weeks of age, and the other three groups were identified at 15 weeks of age. A low, medium and high dose intervention was given to rosiglitazone, and a group of untreated type 2 diabetes was given as a control group. Rosiglitazone was dissolved in 0.9% physiological saline to form a desired concentration of suspension. The low dose group was given 1mg/ (kg. D) every day. The medium dose group was given 3.3mg/ (kg d) every day, and the high dose group was given 10mg/ (kg. D) every day. Gavage, the diabetic control group and the normal group C57 mice were given the same dose of normal saline for 3 months. After treatment, the following tests were performed: 1, the body mass, fasting blood glucose and fasting insulin level were monitored weekly, and the related insulin resistance index was calculated; 2, the behavior changes of mice were observed by water maze and dark experiment; 3, Western and RT-PC were observed. The R method was used to determine the PPAR gamma, mRNA and protein levels of IDE in the hippocampus of mice. 4, the brain tissue sections were stained with HE, Nissl staining, and the changes of neuron morphology and Nissl body were observed under the microscope. 5, the expression of PPAR gamma, IDE, and A beta in the brain tissue of mice was measured by immunochemistry. Results: 1, the mass of mice in each group, fasting blood glucose, insulin and islets of insulin and islet. Comparison of the level of vegetal resistance index: body mass, fasting blood glucose, insulin and insulin resistance at all weeks of age of KKAy mice were higher than that of C57 mice in the control group (P 0.05). Compared with the model control group, there was no significant difference in body mass between the prophylaxis and intervention groups (P0.05), fasting blood glucose, insulin and insulin resistance levels were significant. Decrease (P0.05), high dose effect is more significant.2, mice Behavior Comparison in each group: water maze test results show that compared with the normal control group, the escape latency of the model control group was significantly prolonged, and the number of wear stage decreased significantly (P0.05), compared with the model control group, the incubation period of rosiglitazone intervention and prevention group was significantly reduced. The test results showed that the dark latency of the mice in the model group was significantly shortened and the number of errors increased significantly (P0.05) compared with the normal control group, and the latency and error times of rosiglitazone were significantly improved (P0.05), and the effect of high dose was particularly significant (.3, PPA), PPA in the hippocampus, and PPA in the hippocampus. The level of mRNA and protein of R gamma and IDE: the mRNA and protein levels of PPARy and IDE in the hippocampus of the model control group decreased significantly (P0.05). The mRNA and protein levels of PPARy and IDE increased significantly after the prophylaxis and intervention of rosiglitazone (P 0.05). In the hippocampus of the mice, the morphological structure of the neurons was not remarkable, the nucleus shape was round, the structure of the cell was clear and orderly. The part of the hippocampus tissue in the model control group was damaged by the morphological structure, the nucleus crinkled, the edge was blurred, the cell structure was loosely arranged, and the rosiglitazone was deformed and even necrotic. Prevention and prognosis, the damage degree of cell morphology and structure in the hippocampus of mice was reduced, loosely arranged, the degree of degeneration and necrosis of neurons reduced and pathological damage improved. Nissl staining: no significant abnormalities were found in the hippocampus neurons in normal control group, and the cell nuclear membrane and nucleolus were clearer; the hippocampus of model control mice In the frontal cortex, the cells in the frontal cortex were arranged to evacuate, the cell space was wide and the Nissl body in the cytoplasm was less. The tissue structure of the mice in the rosiglitazone prevention and intervention group was better than the model mice, the cells were arranged densely and neatly, the Nissl body in the cytoplasm increased.5. The expression of PPAR gamma, IDE and A beta in the brain tissue of the mice was measured by immunochemistry: the normal group was small. The cells in the hippocampus of the rat were arranged closely, the cell body was small, the expression of A beta protein was shallow, and the expression was weak. The cells in the hippocampus of the model control group were loosely arranged, the cell body was large, the expression of A beta was strong positive, the IOD value of PpAa gamma and IDE decreased significantly (P0.05). The IOD value of PPARy and IDE in the mice of rosiglitazone prevention and intervention group was significantly increased, A beta protein showed significant. Reduction (P0.05). Conclusion: IDE participates in the early cognitive impairment induced by insulin resistance. The protective effect of.PPAR gamma agonist on cognitive function may be to prevent and improve the cognitive impairment of KKAy mice by increasing IDE and reducing A beta. The effect of PPARy agonists on PC12 cell APP and A beta in the third part of IDE Background: earlier experiments confirmed that PPAR gamma agonists could prevent and improve the cognitive impairment of KKAy mice by raising IDE and reducing A beta levels. But at the cellular level, the mechanism of the protective action of PPARy agonists on the nerve cells is not clear. Objective: To study the IDE mediated PPAR gamma agonist on the amyloid precursor protein (APP) of PC12 cells (APP) and to the IDE mediated PPAR gamma agonist. The effects of A beta on the potential mechanism of the neuroprotective effect of PPARy agonists. Methods: an undifferentiated PC12 cell line was selected to be induced by nerve growth factor as neuron cell. The pretreatment was treated with 1O mu mol/L rosiglitazone, chloroquine 20 mu mol/L, and T0070907 of 12.5 mu mol/L respectively. The treatment group was significantly more than the control group. PC12 cells were treated with the concentration as ideal concentration. After 24 hours of stable growth, the cells were randomly divided into six groups: the normal control group, the rosiglitazone intervention group, the T0070907 treatment group, the T0070907 preconditioning + rosiglitazone group, the chloroquine treatment group, the chloroquine preconditioning + rosiglitazone group, each group of 6 parallel compounds. RT-PCR and Western blotting were used to detect the expression level of mRNA and protein of PPAR gamma, IDE, APP and so on, and the level of A beta in the supernatant of cell culture liquid was detected with ELISA method. Results: 1, the PPARy and IDE mRNA and eggs of the rosiglitazone intervention group were compared with the normal control group. The white content increased significantly (P 0.05), and the content of mRNA and protein in APP decreased significantly (P0.05). 2, there was no significant difference in the mRNA and protein content of PPAR gamma, IDE and APP (P0.05) compared with the T0070907 treatment group and the combination of T0070907 and rosiglitazone combined treatment group. 3, chloroquine and rosiglitazone were treated with chloroquine and rosiglitazone in combination with the chloroquine treatment group. The content of mRNA and protein in Y increased significantly. The mRNA and protein content of IDE and APP had no significant statistical difference (P 0.05). 4, the content of A beta in the supernatant of the culture liquid of rosiglitazone intervention group decreased significantly compared with the normal control group (P0.05), and no significant statistical difference was found in the A beta content of the supernatant of other groups (P0.05). On the other hand, PPARy agonists can induce the expression of DDE and promote the degradation of APP and A beta. However, the protective effect of PPARy agonists on IDE induced neuronal damage can be antagonized by the PPARy inhibitor T0070907 and chloroquine, a IDE inhibitor, indicating that the protective mechanism of the PPAR gamma agonist's nerve cell damage is to participate in the modulation by PPARy activation IDE pathway. The festival.

【學位授予單位】：東南大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R587.2

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