本文選題：阻塞性睡眠呼吸暫停低通氣綜合征 + 胰島素抵抗��； 參考：《蘭州大學(xué)》2016年博士論文

【摘要】：研究表明,阻塞性睡眠呼吸暫停低通氣綜合征(OSAHS)患者中糖代謝紊亂及糖尿病的發(fā)病率明顯高于非OSAHS患者,進(jìn)一步的研究提示OSAHS是胰島素抵抗(IR)及糖尿病的獨(dú)立危險(xiǎn)因素。另外,IR及糖尿病的發(fā)生發(fā)展與內(nèi)源性大麻素系統(tǒng)(ECS)關(guān)系密切,ECS的過(guò)度持久的活化是導(dǎo)致IR及糖尿病的重要原因,而抑制ECS活性的治療可以有效緩解IR及糖尿病。但OSAHS患者ECS是否發(fā)生變化,以及ECS是否與OSAHS并發(fā)糖代謝紊亂有關(guān),目前尚未見(jiàn)到相關(guān)的研究報(bào)道。因此,為了明確上述問(wèn)題,特開(kāi)展本研究,內(nèi)容分為兩個(gè)部分,第一部分為臨床研究,初步探討了OSAHS患者的糖代謝狀態(tài)及其與ECS的關(guān)系,研究共納入OSAHS患者64名(輕度18例,中度24例,重度22例),健康對(duì)照24例。測(cè)量受試者體塊指數(shù)(BMI)、腰圍、空腹血脂、血糖、血胰島素、穩(wěn)態(tài)模型評(píng)估的胰島素抵抗指數(shù)(HOMA-IR)、多導(dǎo)睡眠圖監(jiān)測(cè)指標(biāo)及外周血單個(gè)核細(xì)胞(PBMC)內(nèi)源性大麻素Ⅰ型(CB1)受體蛋白表達(dá)情況。結(jié)果表明,相對(duì)于對(duì)照組,OSAHS患者糖代謝紊亂的發(fā)生率明顯升高,且HOMA-IR、呼吸暫停低通氣指數(shù)(AHI)及PBMC的CB1受體蛋白表達(dá)水平彼此之間呈顯著正相關(guān)關(guān)系。為了進(jìn)一步明確OSAHS對(duì)糖代謝及ECS影響的分子機(jī)制,本研究的第二部分內(nèi)容通過(guò)建立OSAHS的動(dòng)物模型,探索間歇性低氧(IH)對(duì)大鼠體重增長(zhǎng)、糖代謝指標(biāo)、骨骼肌細(xì)胞超微結(jié)構(gòu)、骨骼肌胰島素信號(hào)傳導(dǎo)通路的關(guān)鍵組分GLUT4及ECS的重要組分CB1受體表達(dá)的影響。結(jié)果表明,IH狀態(tài)下,大鼠體重增長(zhǎng)減緩,HOMA-IR升高,同時(shí)大鼠骨骼肌細(xì)胞線粒體等超微結(jié)構(gòu)出現(xiàn)損傷,骨骼肌細(xì)胞膜表面GLUT4、總GLUT4在基因和蛋白質(zhì)水平表達(dá)均明顯減少而CB1受體表達(dá)在基因和蛋白質(zhì)水平均明顯增加。相對(duì)于單純IH組,在IH處置同時(shí)給予CB1受體拮抗劑利莫那班,則大鼠體重增長(zhǎng)逐漸恢復(fù)正常,HOMA-IR下降,同時(shí)大鼠骨骼肌線粒體等超微結(jié)構(gòu)損傷減輕,膜表面GLUT4、總GLUT4表達(dá)升高而CB1受體表達(dá)水平降低。本研究結(jié)果提示:OSAHS患者易于發(fā)生IR及糖代謝紊亂,且與伴隨于OSAHS的ECS狀態(tài)活化密切相關(guān)。IH引起的組織GLUT4表達(dá)減少及CB1受體表達(dá)增多可能是OSAHS引起糖代謝紊亂及IR的重要機(jī)制,CB1受體拮抗劑可以減輕IH導(dǎo)致的上述異常,有望在緩解OSAHS引起的糖代謝紊亂中起一定作用。
[Abstract]:The incidence of glucose metabolism disorder and diabetes mellitus in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) is significantly higher than that in non-OSAHS patients. Further studies suggest that OSAHS is an independent risk factor for insulin resistance and diabetes. In addition, the occurrence and development of IR and diabetes mellitus are closely related to endogenous cannabinoid system. The excessive and persistent activation of endogenous cannabinoid system is an important cause of IR and diabetes, and the treatment of inhibiting the activity of ECS can effectively relieve IR and diabetes. However, whether ECS changes in patients with OSAHS and whether ECS is associated with OSAHS complicated with glucose metabolism disorder has not been reported. Therefore, in order to clarify the above problems, this study is divided into two parts. The first part is a clinical study, which preliminarily discusses the status of glucose metabolism and the relationship between glucose metabolism and ECS in patients with OSAHS. The study included 64 patients with OSAHS (18 mild cases). Moderate 24 cases, severe 22 cases, healthy control 24 cases. Body mass index (BMI), waist circumference, fasting blood lipid, blood glucose and insulin were measured. Homeostasis model was used to evaluate the expression of endogenous cannabinoid type I (CB1) receptor protein in HOMA-IRI, polysomnography and peripheral blood mononuclear cells (PBMCs). The results showed that the incidence of glucose metabolism disorder in OSAHS patients was significantly higher than that in the control group, and there was a significant positive correlation between HOMA-IRI, apnea hypopnea index (AHI) and CB1 receptor protein expression of PBMC. In order to further clarify the molecular mechanism of the effects of OSAHS on glucose metabolism and ECS, the second part of this study was to establish an animal model of OSAHS to explore the effects of intermittent hypoxia on body weight, glucose metabolism and ultrastructure of skeletal muscle cells in rats. Effects of key components of insulin signal transduction pathway in skeletal muscle on the expression of GLUT4 and CB1 receptor, an important component of ECS. The results showed that under the condition of IH, the weight gain of rats slowed down the increase of HOMA-IR, and the ultrastructure of mitochondria of skeletal muscle cells was damaged. GLUT4, total GLUT4 expression at gene and protein level were significantly decreased, while CB1 receptor expression was significantly increased at gene and protein levels on skeletal muscle cell membrane. Compared with the pure IH group, the weight gain of the CB1 receptor antagonist rimonabine was gradually reduced, and the damage of mitochondria and mitochondria of skeletal muscle was reduced, compared with that in the pure IH group. On the surface of GLUT4, the expression of total GLUT4 increased and the expression of CB1 receptor decreased. The results of this study suggest that patients with OSAHS are prone to IR and glucose metabolism disorders. The decrease of GLUT4 expression and the increase of CB1 receptor expression in tissues induced by ECS state activation associated with OSAHS may be an important mechanism of glycometabolism and IR induced by OSAHS. CB1 receptor antagonist can attenuate these abnormalities induced by IH. It is expected to play a role in alleviating the disorder of glucose metabolism caused by OSAHS.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R766;R587.1
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本文編號(hào)：1976057