本文選題：胰島素抵抗　切入點(diǎn)：脂肪細(xì)胞　出處：《南京醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：目的:脂肪組織中巨噬細(xì)胞分泌的炎癥因子可明顯改變脂肪細(xì)胞功能,誘導(dǎo)炎癥反應(yīng),降低胰島素敏感性。然而,關(guān)于脂肪組織中巨噬細(xì)胞分泌的微囊泡在巨噬細(xì)胞和脂肪細(xì)胞間信號(hào)傳遞中的作用尚未明確。但已有研究發(fā)現(xiàn),單核巨噬細(xì)胞分泌的微囊泡可上調(diào)人呼吸道上皮細(xì)胞炎癥介質(zhì)的合成,在炎性疾病的發(fā)生中起一定的作用。所以,本研究主要探討炎性巨噬細(xì)胞分泌的微囊泡對(duì)人脂肪細(xì)胞胰島素抵抗的影響。方法:通過(guò)刺激M1型和M2型THP-1巨噬細(xì)胞產(chǎn)生各自的微囊泡,將這些微囊泡分別與人的原代成熟脂肪細(xì)胞和由人前脂肪細(xì)胞分化而來(lái)的成熟脂肪細(xì)胞共培養(yǎng),然后通過(guò)Western Blot方法檢測(cè)人脂肪細(xì)胞中Akt磷酸化水平;運(yùn)用2-NBDG評(píng)估人脂肪細(xì)胞對(duì)葡萄糖的攝取。同時(shí),我們還提取了被處理的人脂肪細(xì)胞的質(zhì)膜,通過(guò)Western Blot方法檢測(cè)細(xì)胞膜上GLUT4表達(dá)水平;通過(guò)核萃取和Western Blot方法檢測(cè)NF-κB核轉(zhuǎn)運(yùn)水平。結(jié)果:與M2型巨噬細(xì)胞分泌的微囊泡(M2 MVs)相比,M1型巨噬細(xì)胞分泌的微囊泡(M1 MVs)可明顯減少人脂肪細(xì)胞中磷酸化Akt水平。通過(guò)2-NBDG檢測(cè)人脂肪細(xì)胞對(duì)糖的攝取,我們發(fā)現(xiàn)用M1 MVs處理人脂肪細(xì)胞后,人脂肪細(xì)胞對(duì)胰島素依賴的葡萄糖攝取減少,而用M2 MVs處理人脂肪細(xì)胞后,人脂肪細(xì)胞對(duì)胰島素依賴的葡萄糖攝取增加。與M2 MVs相比,用M1 MVs處理人脂肪細(xì)胞后,可引起人脂肪細(xì)胞NF-κB核轉(zhuǎn)位增加,Akt磷酸化和GLUT4膜轉(zhuǎn)運(yùn)減少,而這些改變可被NF-κB的特異性抑制劑——BAY 11-7085逆轉(zhuǎn)。結(jié)論:促炎的M1型巨噬細(xì)胞分泌的微囊泡可能是肥胖引起的胰島素抵抗的原因之一,其機(jī)制可能是通過(guò)激活NF-κB,減少人脂肪細(xì)胞胰島素信號(hào)轉(zhuǎn)導(dǎo),降低細(xì)胞葡萄糖攝取。目的:探討艾塞那肽對(duì)肥胖2型糖尿病患者內(nèi)臟脂肪的影響。方法:將36名單用二甲雙胍治療血糖控制不達(dá)標(biāo)的肥胖2型糖尿病患者隨機(jī)分別接受艾塞那肽+二甲雙胍治療(GLP-1組)或阿卡波糖+二甲雙胍治療(對(duì)照組)3個(gè)月。觀察兩組患者試驗(yàn)前后內(nèi)臟脂肪含量的變化,以及空腹血糖、糖化血紅蛋白、空腹胰島素、血脂、體重指數(shù)和炎癥因子的改變。結(jié)果:GLP-1組患者的內(nèi)臟脂肪含量試驗(yàn)后較試驗(yàn)前明顯減少(前:17947±5804mm2后:13717士3628mm2,P=0.001),而對(duì)照組內(nèi)臟脂肪含量試驗(yàn)前后無(wú)明顯變化(P = 0.197)。試驗(yàn)后,GLP-1組患者內(nèi)臟脂肪含量較對(duì)照組更低(P=0.043)。兩組患者試驗(yàn)后的血糖控制和胰島素抵抗較試驗(yàn)前均明顯改善,HbA1c(GLP-1 組:前 9.72±1.38%后 7.09±0.60%,P0.001;對(duì)照組:前 9.46±1.25%后 7.42±0.84%,P0.001),LN(HOMA-IR)(GLP-1 組:前 1.58±0.40后 1.01±0.33,P0.001;對(duì)照組:前 1.53±0.57后 1.10±0.33,P=0.003)。但試驗(yàn)后,兩組間HbA1c和LN(HOMA-IR)比較無(wú)明顯差異。GLP-1組試驗(yàn)后TNF-α,IL-6和瘦素較試驗(yàn)前明顯降低,脂聯(lián)素明顯升高(P0.05),而對(duì)照組試驗(yàn)前后均無(wú)明顯改變。試驗(yàn)后,兩組間TNF-α,IL-6和瘦素水平無(wú)明顯不同,而GLP-1組脂聯(lián)素水平較對(duì)照組更高(P = 0.025)。結(jié)論:艾塞那肽在控制血糖同時(shí),還可減少肥胖糖尿病患者的內(nèi)臟脂肪含量、改善肥胖患者的胰島素抵抗和炎癥狀態(tài)。
[Abstract]:Objective: inflammatory cytokines secreted by macrophages in adipose tissue can markedly alter adipocyte function, inducing inflammation, reduce insulin sensitivity. However, on macrophages in adipose tissue secretion were soaked in macrophages and adipocytes in signal transduction are not yet clear. But studies have found that the synthesis of microencapsulated mononuclear macrophage foam on the epithelial cells of human respiratory tract inflammatory mediators, play a role in inflammatory diseases. Therefore, this study focused on the inflammatory macrophage foam microcapsule effects on insulin resistance in human adipose cells. Methods: the vesicles through the stimulation of M1 type and M2 type THP-1 macrophages, these microvesicles were primary adipocytes and the differentiation of human preadipocytes to mature adipocytes were cultured, and then through the Western Blot Method for detection of human fat cells in Akt phosphorylation; use of glucose uptake in 2-NBDG assessment of fat cells. At the same time, we also extracted human adipocytes treated membrane, through the cell membrane to detect Western Blot method on the expression level of GLUT4; through nuclear extraction and Western Blot method to detect NF- kappa B nuclear translocation. Results: Microcystis secretion and M2 macrophages (M2 MVs) compared to the global, M1 type macrophage foam microcapsules (M1 MVs) can significantly reduce the human fat cells in Akt phosphate level. Based on the detection of glucose uptake in human adipocytes 2-NBDG, we found that M1 MVs treated human fat cells, glucose uptake of people fat cells to insulin dependent decrease, and M2 MVs in human adipocytes, glucose uptake in human adipose cells to insulin dependent increase. Compared with M2 MVs, M1 MVs treated fat cells, can cause Human fat cells NF- kappa B nuclear translocation increased Akt phosphorylation and GLUT4 membrane decreased, and these changes may be a specific inhibitor of NF- kappa B -- BAY 11-7085. Conclusion: the reversal of microencapsulated M1 macrophages inflammatory secretion may be one of the reasons for global obesity induced insulin resistance and its possible mechanism through the activation of NF- kappa B, reduced insulin signal transduction in fat cells, reduce the cell glucose uptake. Objective: To evaluate the effect of exenatide on type 2 diabetes mellitus patients with visceral fat obesity. Methods: 36 list with metformin insufficientlycontrolled blood glucose in obese patients with type 2 diabetes were randomized to receive exenatide and metformin the treatment (group GLP-1) or acarbose and metformin treatment (control group) for 3 months. To observe the changes of visceral fat content of two groups of patients before and after the test, and fasting blood glucose, glycosylated hemoglobin, fasting insulin, Blood lipid, body mass index and inflammatory factor changes. Results: visceral fat content test in GLP-1 group were significantly decreased after more tests before (before: 17947 + 5804mm2 13717 + 3628mm2, P=0.001), while the control group before and after the test of visceral fat content had no significant change (P = 0.197). After the test, patients in group GLP-1 visceral fat content is lower than the control group (P=0.043). The two groups of patients after the test of glucose control and insulin resistance test were significantly improved, HbA1c (group GLP-1: 9.72 + 1.38% 7.09 + 0.60%, P0.001; control group: 9.46 + 1.25% 7.42 + 0.84%, P0.001), LN (HOMA-IR) (group GLP-1: 1.58 + 0.40 1.01 + 0.33, P0.001; control group: 1.53 + 0.57 1.10 + 0.33, P=0.003). But after the experiment, two groups of HbA1c and LN (HOMA-IR) was not significantly different between.GLP-1 group after the test of TNF- alpha, IL-6 and leptin were tested decreased obviously adiponectin was significantly increased (P0.05 ), while the control group had no obvious change before and after the test. After the test, two groups of TNF- alpha, IL-6 and leptin levels were not significantly different, while adiponectin levels higher than the control group GLP-1 group (P = 0.025). Conclusion: exenatide in glycemic control at the same time, also can reduce the content of visceral fat in obese patients. Diabetes in obese patients, improve insulin resistance and inflammation.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R58

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本文編號(hào)：1622140