本文選題：老年 + 糖尿病　； 參考：《鄭州大學(xué)》2015年博士論文

【摘要】：背景近年來,老年2型糖尿病(type 2 diabetes mellitus,T2DM)發(fā)病率持續(xù)增高,且隨著發(fā)病時(shí)間的延長(zhǎng),相關(guān)的慢性并發(fā)癥亦隨之增加,給患者及社會(huì)帶來了較大的經(jīng)濟(jì)負(fù)擔(dān),使患者生活質(zhì)量下降。心血管病(cardiovascular disease,CVD)和糖尿病是等危癥,且絕大多數(shù)的2型糖尿病患者死于心血管疾病,在糖尿病心血管病的發(fā)病機(jī)制中,脂肪因子抵抗素及脂聯(lián)素與其有一定相關(guān)性,脂聯(lián)素通過抗炎性反應(yīng)、抗氧化應(yīng)激等多種途徑保護(hù)血管內(nèi)皮細(xì)胞,但抵抗素與糖尿病及心血管病發(fā)生的關(guān)系中,相關(guān)的研究意見不統(tǒng)一。在糖尿病群體中,糖尿病神經(jīng)痛即痛性糖尿病神經(jīng)病變(painful diabetic neuropathy,PDN)為表現(xiàn)的慢性并發(fā)癥,臨床癥狀主要為肢體皮膚的燒灼痛、自發(fā)痛和痛覺過敏等,進(jìn)而影響患者的睡眠、精神心理障礙等,并誘發(fā)不良心血管事件發(fā)生;有關(guān)神經(jīng)痛的發(fā)病機(jī)制,目前報(bào)道的主要集中在脊髓神經(jīng)元突觸可塑性,而大腦前扣帶回(Anterior cingulate cortex,ACC)對(duì)于神經(jīng)痛所起的作用相關(guān)研究較少。目的:回顧性分析老年2型糖尿病患者合并慢性并發(fā)癥發(fā)生率及發(fā)病時(shí)間的相關(guān)影響因素;探討在老年2型糖尿病患者中,心血管病的發(fā)病率及死亡率與抵抗素、脂聯(lián)素水平的關(guān)系;檢測(cè)患糖尿病神經(jīng)痛大鼠的ACC中谷氨酸能傳遞的變化。對(duì)象和方法:本研究選擇在鄭州大學(xué)第一附屬醫(yī)院老年內(nèi)分泌科住院的患者,年齡均≥60歲,對(duì)其人口學(xué)特征、相關(guān)病史及抵抗素、脂聯(lián)素等實(shí)驗(yàn)室檢查結(jié)果進(jìn)行分析。制作患糖尿病神經(jīng)痛的大鼠模型,進(jìn)行相關(guān)神經(jīng)痛的研究并就實(shí)驗(yàn)結(jié)果進(jìn)行分析。具體方法如下。1)收集149例住院的老年2型糖尿病患者資料,回顧性分析相關(guān)數(shù)據(jù)資料,用X2檢驗(yàn)或Fisher精確概率檢驗(yàn)行分類資料的比較;正態(tài)分布的計(jì)量資料行2樣本均數(shù)比較的t檢驗(yàn),如不符合正態(tài)分布,行獨(dú)立樣本的秩和檢驗(yàn);非條件Logistic回歸模型進(jìn)行多因素的分析。2)選擇60例老年2型糖尿病患者,患者年齡為60-68歲,中位年齡為64歲,糖尿病平均病程為10.2±2.4年,酶聯(lián)免疫吸附法測(cè)定抵抗素、脂聯(lián)素水平,在24月的隨訪中,記錄致死性心血管病和非致死性心血管病事件,多因素Cox回歸分析心血管病的發(fā)病風(fēng)險(xiǎn),探討老年2型糖尿病抵抗素、脂聯(lián)素水平與心血管病的關(guān)系。3)給大鼠注射鏈脲佐菌素(streptozotocin,STZ)誘導(dǎo)高血糖、熱痛覺過敏和機(jī)械性痛覺過敏;ACC內(nèi)微量注射相關(guān)藥物前后,進(jìn)行行為學(xué)測(cè)試;制作ACC薄片并行全膜片鉗記錄,分析谷氨酸能傳遞特點(diǎn),應(yīng)用免疫印跡技術(shù)檢測(cè)在糖尿病大鼠ACC組織PKMζ和磷酸化的PKMζ表達(dá)。用配對(duì)、非配對(duì)T檢驗(yàn)或雙因素方差分析對(duì)實(shí)驗(yàn)結(jié)果進(jìn)行組間比較。結(jié)果:1)149例老年2型糖尿病患者中,確診慢性并發(fā)癥的中位年齡為65歲(四分位數(shù)間距60-72歲),慢性并發(fā)癥的發(fā)病人數(shù)為118例,發(fā)生率是79.19%;多因素分析結(jié)果提示病程、HDL及超敏C反應(yīng)蛋白是老年2型糖尿病合并慢性并發(fā)癥的獨(dú)立危險(xiǎn)因素;確診糖尿病后合并慢性并發(fā)癥的中位時(shí)間為5年,糖尿病病程10年、無糖尿病家族史、有吸煙史及HDL降低者更早發(fā)生慢性并發(fā)癥。2)根據(jù)患者血清抵抗素中位值293.25pg/ml進(jìn)行分組,結(jié)果顯示性別分布、糖尿病病程、胰島素治療、體重指數(shù)(body mass index,BMI)、生化結(jié)果和既往心血管事件均無顯著差異。在24個(gè)月的隨訪中,有6例(10.00%)老年2型糖尿病患者死于心血管疾病,14例(23.33%)患者發(fā)生了一次非致死性心血管病。血清抵抗素水平≥293.25pg/ml組在致死性和非致死性心血管病變的聯(lián)合終點(diǎn)發(fā)生率明顯增高(P=0.001)。多因素Cox回歸分析顯示,抵抗素水平大于等于中位值者是聯(lián)合終點(diǎn)事件的獨(dú)立危險(xiǎn)因素(HR:5.73,95%CI:1.91-17.23)。根據(jù)血清脂聯(lián)素中位值4.25μg/ml對(duì)患者進(jìn)行分組并統(tǒng)計(jì)分析,結(jié)果提示脂聯(lián)素水平4.25μg/ml組BMI及CRP水平高于≥4.25μg/ml組;24個(gè)月的隨訪觀察中,4.25μg/ml組的致死性和非致死性心血管病的聯(lián)合終點(diǎn)發(fā)生率明顯增高(P0.05),且該組患者更早發(fā)生聯(lián)合終點(diǎn)事件。3)患糖尿病神經(jīng)痛的大鼠ACC神經(jīng)元的基礎(chǔ)谷氨酸能傳遞有顯著增高,且ACC神經(jīng)元有突觸前谷氨酸釋放增加和突觸后谷氨酸受體傳導(dǎo)增強(qiáng)。本研究發(fā)現(xiàn)在ACC中,磷酸化的蛋白激酶Mζ(PKMζ)升高,但總PKMζ表達(dá)沒增加。在STZ注射的大鼠ACC區(qū)微量注射PKMζ抑制劑ZIP可減弱谷氨酸能傳遞上調(diào)和疼痛行為表現(xiàn)。結(jié)論:1)隨著糖尿病病程的延長(zhǎng),慢性并發(fā)癥的發(fā)生率亦增加,但病程短、無糖尿病家族史、HDL降低及吸煙者更早發(fā)生慢性并發(fā)癥,因此要提高健康體檢意識(shí),增加糖尿病及其慢性并發(fā)癥的知曉率及診治率,全民普及糖尿病教育知識(shí),并對(duì)糖尿病危險(xiǎn)因素要及時(shí)干預(yù)。2)根據(jù)抵抗素和脂聯(lián)素水平可評(píng)估老年2型糖尿病的預(yù)后,并可對(duì)老年2型糖尿病患者心血管病的危險(xiǎn)分層提供依據(jù)。3)在患糖尿病神經(jīng)痛的嚙齒動(dòng)物中,它們的ACC神經(jīng)元有中樞致敏作用,可能是糖尿病神經(jīng)痛患者負(fù)面影響因素的基礎(chǔ)。
[Abstract]:In recent years, the incidence of elderly type 2 diabetes (type 2 diabetes mellitus, T2DM) continues to increase, and with the prolongation of the onset of the disease, the associated chronic complications, Yi Suizhi increased, brought a greater economic burden to the patients and the society, and reduced the quality of life of the patients. Cardiovascular disease (cardiovascular disease, CVD) and diabetes are in danger. Most patients with type 2 diabetes die from cardiovascular disease. In the pathogenesis of diabetic cardiovascular disease, the adiponectin and adiponectin are related to it. Adiponectin protects vascular endothelial cells through anti-inflammatory response, antioxidant stress and many other pathways, but resistin is associated with diabetes and cardiovascular disease. In the diabetic group, diabetic neuropathic pain, which is painful diabetic neuropathy (PDN), is a chronic complication. The main clinical symptoms are burning pain in the body skin, self pain and hyperalgesia, and then affecting the patients' sleep and mental mental disorders, and so on. The pathogenesis of adverse cardiovascular events, the pathogenesis of neuralgia, is mainly focused on synaptic plasticity in spinal neurons, and the role of Anterior cingulate cortex (ACC) for neuralgia is less studied. Objective: To review the retrospective analysis of chronic complications in elderly patients with type 2 diabetes. The related factors of birth rate and time of onset; the relationship between the incidence of cardiovascular disease and the mortality of cardiovascular disease and the level of adiponectin in the elderly patients with type 2 diabetes; the changes in glutamate energy transfer in ACC of diabetic rats with neuropathic pain. Objects and methods: This study was selected at the First Affiliated Hospital of Zhengzhou University. The patients in the secretory department were older than 60 years old. Their demographic characteristics, related history and resistin, adiponectin and other laboratory results were analyzed. The rat model of diabetic neuropathic pain was made, the related neuralgia was studied and the experimental results were analyzed. 149 cases of aged 2 diabetes were collected in.1). Patients with disease data, retrospective analysis of relevant data, X2 test or Fisher accurate probability test for the comparison of the classification data; the normal distribution of the measurement data of the 2 samples are compared with the t test, such as the normal distribution, the rank sum test of independent samples; the non conditional Logistic regression model for multiple factors analysis.2) selection of the 60 cases of old age In patients with type 2 diabetes, the age of the patients was 60-68 years, the median age was 64 years, the average course of diabetes was 10.2 + 2.4 years. The enzyme linked immunosorbent assay was used to determine the resistin and adiponectin level. During the 24 month follow-up, the fatal cardiovascular and non fatal cardiovascular events were recorded, and the risk of cardiovascular disease was analyzed by multiple factor Cox regression. Aged type 2 diabetic resistin, adiponectin level and cardiovascular disease.3) induced hyperglycemia, hyperalgesia and mechanical hyperalgesia of streptozotocin (STZ) in rats; behavior test was performed before and after microinjection of related drugs in ACC; ACC thin slice parallel full patch clamp recording and analysis of glutamic acid transmission were made. The expression of PKM zeta and phosphorylation of PKM zeta in ACC tissues of diabetic rats were detected by immunoblotting. The results were compared with the results of paired, non paired T test or double factor variance analysis. Results: 1) the median age of diagnosis of chronic concomysis in 149 elderly patients with type 2 diabetes was 65 years (60-72 years of four). The incidence of chronic complications was 118, the incidence of which was 79.19%. The multifactor analysis indicated the course of disease. HDL and hypersensitive C reactive protein were independent risk factors for chronic complications of type 2 diabetes in the elderly. The median time for the diagnosis of diabetes with chronic complications was 5 years, the course of diabetes was 10 years, no family history of diabetes, and smoking. History and the early onset of chronic complication.2 in the HDL depression group were grouped according to the median 293.25pg/ml of the patient's serum resistin. The results showed that the sex distribution, the course of diabetes, the insulin treatment, the body mass index (body mass index, BMI), biochemical results and previous cardiovascular events were not significantly different. In the 24 month follow-up, there were 6 cases (10%) of the elderly. Patients with type 2 diabetes died of cardiovascular disease, and 14 patients (23.33%) had a non fatal cardiovascular disease. The incidence of combined endpoints of the serum resistin level in the 293.25pg/ml group was significantly higher in both fatal and non fatal cardiovascular diseases (P=0.001). The multifactor Cox regression analysis showed that the level of resistin was greater than the median value. The independent risk factor of the joint endpoint (HR:5.73,95%CI:1.91-17.23). The patients were grouped and analyzed according to the serum adiponectin level of 4.25 micron g/ml. The results showed that the level of BMI and CRP in the adiponectin level was higher than that of the group of more than 4.25 mu g/ml; the fatal and non lethal cardiovascular system of the 4.25 mu g/ml group was observed at 24 months of follow-up. The incidence of the joint endpoint increased significantly (P0.05), and the group of patients with the joint endpoint occurred earlier.3) the basal glutamate transfer of ACC neurons in the rats with diabetic neuralgia was significantly higher, and the ACC neurons had pre synaptic glutamic acid release and the postsynaptic glutamate receptor conduction enhancement. This study found phosphoric acid in ACC. The expression of protein kinase M zeta (PKM zeta) increased, but the expression of total PKM zeta did not increase. Microinjection of PKM zeta inhibitor ZIP in ACC region of rats injected with STZ could weaken the expression of glutamate energy transfer and pain. Conclusion: 1) the incidence of chronic complications is also increased with the prolongation of the course of diabetes, but the course of the disease is short, no family history of diabetes, HDL decrease and Smokers have chronic complications earlier. Therefore, we should improve the awareness of health examination, increase the awareness of diabetes and its chronic complications and the rate of diagnosis and treatment, popularize the education knowledge of diabetes, and intervene.2 in time for the risk factors of diabetes. According to the level of resistin and adiponectin, the prognosis of type 2 diabetes in the aged can be evaluated, and 2 of the elderly can be used. The risk stratification of cardiovascular disease in patients with diabetes mellitus provides a basis for.3) in the rodents with diabetic neuropathic pain, their ACC neurons have central sensitization, which may be the basis for the negative influence factors of diabetic neuropathic pain.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R587.2

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3 北京協(xié)和醫(yī)院 梁曉春;對(duì)中醫(yī)治糖尿病并發(fā)癥研究的思考[N];中國(guó)中醫(yī)藥報(bào);2011年

4 劉燕玲;肥胖是糖尿病的源頭[N];健康報(bào);2006年

5 仝小林;糖尿病慢性并發(fā)癥論治[N];中國(guó)中醫(yī)藥報(bào);2003年

6 汪敏;糖尿病皮膚易損元兇找到[N];衛(wèi)生與生活報(bào);2003年

7 林蘭;中西醫(yī)結(jié)合治療糖尿病的前景[N];中國(guó)中醫(yī)藥報(bào);2007年

8 北京協(xié)和醫(yī)院中醫(yī)科主任 梁曉春;糖尿病周圍神經(jīng)病變的中西醫(yī)治療進(jìn)展[N];中國(guó)醫(yī)藥報(bào);2009年

9 本報(bào)記者 劉艷芳;糖尿病干預(yù)不能忽視抗氧化[N];中國(guó)食品報(bào);2012年

10 譚小月;糖尿病與腎病關(guān)系研究的新進(jìn)展[N];中國(guó)中醫(yī)藥報(bào);2004年

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3 高泓;參芪復(fù)方調(diào)控糖尿病血管PI3-K/Akt通路的實(shí)驗(yàn)研究[D];成都中醫(yī)藥大學(xué);2009年

4 張冬梅;特發(fā)性1型糖尿病的臨床研究[D];中南大學(xué);2003年

5 王寬宇;早期離斷配合外用中藥藥膜治療糖尿病足的實(shí)驗(yàn)研究和臨床觀察[D];黑龍江中醫(yī)藥大學(xué);2010年

6 李純;抑制神經(jīng)酰胺合成對(duì)糖尿病大鼠內(nèi)皮功能紊亂及動(dòng)脈粥樣硬化形成的影響[D];中南大學(xué);2011年

7 郭志新;血管緊張素Ⅱ受體拮抗劑對(duì)糖尿病大鼠腎臟的保護(hù)作用及其作用機(jī)制的研究[D];天津醫(yī)科大學(xué);2002年

8 宋莉莉;糖尿病對(duì)血管性癡呆認(rèn)知功能影響的實(shí)驗(yàn)研究[D];第二軍醫(yī)大學(xué);2004年

9 姜兆順;基于結(jié)構(gòu)化住院病歷采集系統(tǒng)對(duì)糖尿病及血管并發(fā)癥辨證論治規(guī)律的研究[D];中國(guó)中醫(yī)研究院;2005年

10 郝賢;降糖消脂湯對(duì)2型糖尿病大鼠胰島素抵抗影響機(jī)制實(shí)驗(yàn)研究[D];黑龍江中醫(yī)藥大學(xué);2006年

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3 吳迪;電針治療糖尿病周圍神經(jīng)病的臨床觀察及其作用機(jī)制的實(shí)驗(yàn)研究[D];黑龍江中醫(yī)藥大學(xué);2009年

4 侯亞利;2型糖尿病患者心臟結(jié)構(gòu)和功能的變化[D];蘭州大學(xué);2010年

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6 張麗;2型糖尿病患者的肺功能變化及其相關(guān)因素分析[D];新疆醫(yī)科大學(xué);2010年

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8 邱作成;健脾腎化瘀濁法治療糖尿病多發(fā)性周圍神經(jīng)病變的研究[D];新疆醫(yī)科大學(xué);2004年

9 馮智敏;糖尿病對(duì)大鼠正畸牙齒移動(dòng)的影響[D];河北醫(yī)科大學(xué);2006年

10 鄭淑君;胰島素樣生長(zhǎng)因子-1與1型糖尿病大鼠骨骼肌病變的關(guān)系[D];山西醫(yī)科大學(xué);2006年

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