【摘要】：糖尿病（diabetes mellitus，DM）是一組以高血糖為特征的代謝性疾病，已成為威脅人類生命健康的三大危險(xiǎn)性疾病之一。糖尿病腎病是最常見(jiàn)、最嚴(yán)重的糖尿病微血管并發(fā)癥之一，最終導(dǎo)致進(jìn)行性腎功能衰竭，占終末期腎臟疾病新發(fā)病例的40%。在我國(guó)，，糖尿病腎病已經(jīng)成為導(dǎo)致終末期腎臟疾病的第二位病因，并且其發(fā)病率均呈現(xiàn)一個(gè)快速增長(zhǎng)的趨勢(shì)，給人們生活帶來(lái)極大的負(fù)擔(dān)。2型糖尿病占所有確診糖尿病患者的90%以上，因此，如何預(yù)防和治療2型糖尿病腎病已經(jīng)成為醫(yī)學(xué)界急需解決的問(wèn)題。目前認(rèn)為，糖、脂代謝紊亂及其誘導(dǎo)的氧化應(yīng)激是導(dǎo)致2型糖尿病腎病關(guān)鍵誘因。 與高劑量電離輻射不同，LDR誘導(dǎo)機(jī)體適應(yīng)性反應(yīng)，提高機(jī)體抗氧化功能，降低炎癥反應(yīng)。另外，F(xiàn)GF21作為一個(gè)新型藥物在治療2型糖尿病及相關(guān)代謝紊亂疾病上表現(xiàn)出希望。臨床試驗(yàn)證實(shí)，F(xiàn)GF21可持續(xù)控制血糖和血脂，改善胰島素抵抗，提高β-細(xì)胞功能，同時(shí)很少出現(xiàn)常見(jiàn)治療藥物的副作用如低血糖、水腫以及肥胖。本實(shí)驗(yàn)引入LDR及FGF21兩個(gè)關(guān)鍵干預(yù)因素，分別對(duì)輻射與FGF21劑量及干預(yù)時(shí)程進(jìn)行優(yōu)化之后實(shí)現(xiàn)聯(lián)合作用，用以探討兩者聯(lián)用對(duì)于糖尿病腎病的預(yù)防或治療的協(xié)同作用。 本研究采用的實(shí)驗(yàn)方法，包括Western-blot、qRT-PCR、IHC以及ELISA等，從基因、蛋白質(zhì)和組織水平研究LDR（25mGy、50mGy和75mGy）和FGF21（0.5mg/kg、1.5mg/kg和2.5mg/kg）分別處理4周和8周之后，對(duì)糖尿病小鼠的外周血生物化學(xué)指標(biāo)及腎臟組織的不同抗氧化因子（Nrf-2、HO-1、NQO-1、SOD-1）和炎癥因子（ICAM-1、TNF-α和PAI-1）的影響，進(jìn)而選擇二者最佳治療方式，探討將其聯(lián)用后對(duì)2型糖尿病腎病的保護(hù)作用及其機(jī)制。結(jié)果顯示，LDR和FGF21單一處理均能有效延緩2型糖尿病腎臟疾病的進(jìn)程；相比單一處理，二者聯(lián)合作用進(jìn)一步抑制2型糖尿病誘導(dǎo)的腎臟損傷。本研究結(jié)果提示，LDR與FGF21聯(lián)合作用可有效阻止2型糖尿病腎病的發(fā)展，改善糖尿病小鼠的腎臟功能，對(duì)糖尿病腎病有明顯的保護(hù)作用，其機(jī)制可能與機(jī)體血糖降低、改善血脂代謝譜以及抗氧化功能升高有關(guān)，但仍需進(jìn)一步深入探討。
[Abstract]:Diabetes mellitus (diabetes mellitus DM) is a metabolic disease characterized by hyperglycemia, which has become one of the three dangerous diseases threatening human life and health. Diabetic nephropathy is one of the most common and severe diabetic microvascular complications, leading to progressive renal failure, accounting for 40 new cases of end-stage renal disease. In China, diabetic nephropathy has become the second leading cause of end-stage renal disease, and the incidence of diabetic nephropathy has shown a rapid growth trend. Type 2 diabetes accounts for more than 90% of all diagnosed diabetic patients. Therefore, how to prevent and treat type 2 diabetic nephropathy has become an urgent problem in the medical field. It is believed that the disorder of glucose and lipid metabolism and oxidative stress are the key factors leading to type 2 diabetic nephropathy. Different from high dose of ionizing radiation, LDR induces adaptive response, improves antioxidant function and reduces inflammatory response. In addition, FGF21 as a new drug in the treatment of type 2 diabetes mellitus and related metabolic disorders show hope. Clinical trials have proved that FGF21 can sustainably control blood glucose and lipids, improve insulin resistance, and improve 尾 -cell function, while side effects of common therapeutic drugs such as hypoglycemia, edema and obesity are rare. In this experiment, two key intervention factors, LDR and FGF21, were introduced to optimize the dose of radiation and FGF21 and the duration of intervention, respectively, to achieve the combined effect, so as to explore the synergistic effect of the two combined therapy on the prevention or treatment of diabetic nephropathy. The experimental methods used in this study, including Western-blottqRT-PCRHC and ELISA, were used to study the effects of LDR (25mGy, 50mGy and 75mGy) and FGF21 (0.5mgr / kg 1.5mg / kg and 2.5mg/kg) on gene, protein and tissue levels for 4 and 8 weeks, respectively. The effects of different antioxidant factors (Nrf-2HO-1, NQO-1SOD-1) and inflammatory factors (ICAM-1, TNF- 偽 and PAI-1) on peripheral blood biochemical indexes and renal tissue of diabetic mice were studied. To investigate the protective effect and mechanism of combined therapy on type 2 diabetic nephropathy. The results showed that both LDR and FGF21 single treatment could effectively delay the progression of renal disease in type 2 diabetes mellitus, and the combination of them could further inhibit the renal injury induced by type 2 diabetes mellitus. The results suggest that the combination of LDR and FGF21 can effectively prevent the development of type 2 diabetic nephropathy, improve the renal function of diabetic mice, and have an obvious protective effect on diabetic nephropathy, and its mechanism may be related to the decrease of blood glucose. The improvement of lipid metabolism spectrum and the increase of antioxidant function are related, but need to be further discussed.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R587.2;R692

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