老年2型糖尿病及其慢性并发症的相关研究

发布时间：2018-05-18 01:34

本文选题：老年 + 糖尿病　；参考：《郑州大学》2015年博士论文

【摘要】：背景近年来,老年2型糖尿病(type 2 diabetes mellitus,T2DM)发病率持续增高,且随着发病时间的延长,相关的慢性并发症亦随之增加,给患者及社会带来了较大的经济负担,使患者生活质量下降。心血管病(cardiovascular disease,CVD)和糖尿病是等危症,且绝大多数的2型糖尿病患者死于心血管疾病,在糖尿病心血管病的发病机制中,脂肪因子抵抗素及脂联素与其有一定相关性,脂联素通过抗炎性反应、抗氧化应激等多种途径保护血管内皮细胞,但抵抗素与糖尿病及心血管病发生的关系中,相关的研究意见不统一。在糖尿病群体中,糖尿病神经痛即痛性糖尿病神经病变(painful diabetic neuropathy,PDN)为表现的慢性并发症,临床症状主要为肢体皮肤的烧灼痛、自发痛和痛觉过敏等,进而影响患者的睡眠、精神心理障碍等,并诱发不良心血管事件发生;有关神经痛的发病机制,目前报道的主要集中在脊髓神经元突触可塑性,而大脑前扣带回(Anterior cingulate cortex,ACC)对于神经痛所起的作用相关研究较少。目的:回顾性分析老年2型糖尿病患者合并慢性并发症发生率及发病时间的相关影响因素;探讨在老年2型糖尿病患者中,心血管病的发病率及死亡率与抵抗素、脂联素水平的关系;检测患糖尿病神经痛大鼠的ACC中谷氨酸能传递的变化。对象和方法:本研究选择在郑州大学第一附属医院老年内分泌科住院的患者,年龄均≥60岁,对其人口学特征、相关病史及抵抗素、脂联素等实验室检查结果进行分析。制作患糖尿病神经痛的大鼠模型,进行相关神经痛的研究并就实验结果进行分析。具体方法如下。1)收集149例住院的老年2型糖尿病患者资料,回顾性分析相关数据资料,用X2检验或Fisher精确概率检验行分类资料的比较;正态分布的计量资料行2样本均数比较的t检验,如不符合正态分布,行独立样本的秩和检验;非条件Logistic回归模型进行多因素的分析。2)选择60例老年2型糖尿病患者,患者年龄为60-68岁,中位年龄为64岁,糖尿病平均病程为10.2±2.4年,酶联免疫吸附法测定抵抗素、脂联素水平,在24月的随访中,记录致死性心血管病和非致死性心血管病事件,多因素Cox回归分析心血管病的发病风险,探讨老年2型糖尿病抵抗素、脂联素水平与心血管病的关系。3)给大鼠注射链脲佐菌素(streptozotocin,STZ)诱导高血糖、热痛觉过敏和机械性痛觉过敏;ACC内微量注射相关药物前后,进行行为学测试;制作ACC薄片并行全膜片钳记录,分析谷氨酸能传递特点,应用免疫印迹技术检测在糖尿病大鼠ACC组织PKMζ和磷酸化的PKMζ表达。用配对、非配对T检验或双因素方差分析对实验结果进行组间比较。结果:1)149例老年2型糖尿病患者中,确诊慢性并发症的中位年龄为65岁(四分位数间距60-72岁),慢性并发症的发病人数为118例,发生率是79.19%;多因素分析结果提示病程、HDL及超敏C反应蛋白是老年2型糖尿病合并慢性并发症的独立危险因素;确诊糖尿病后合并慢性并发症的中位时间为5年,糖尿病病程10年、无糖尿病家族史、有吸烟史及HDL降低者更早发生慢性并发症。2)根据患者血清抵抗素中位值293.25pg/ml进行分组,结果显示性别分布、糖尿病病程、胰岛素治疗、体重指数(body mass index,BMI)、生化结果和既往心血管事件均无显著差异。在24个月的随访中,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%)患者发生了一次非致死性心血管病。血清抵抗素水平≥293.25pg/ml组在致死性和非致死性心血管病变的联合终点发生率明显增高(P=0.001)。多因素Cox回归分析显示,抵抗素水平大于等于中位值者是联合终点事件的独立危险因素(HR:5.73,95%CI:1.91-17.23)。根据血清脂联素中位值4.25μg/ml对患者进行分组并统计分析,结果提示脂联素水平4.25μg/ml组BMI及CRP水平高于≥4.25μg/ml组;24个月的随访观察中,4.25μg/ml组的致死性和非致死性心血管病的联合终点发生率明显增高(P0.05),且该组患者更早发生联合终点事件。3)患糖尿病神经痛的大鼠ACC神经元的基础谷氨酸能传递有显著增高,且ACC神经元有突触前谷氨酸释放增加和突触后谷氨酸受体传导增强。本研究发现在ACC中,磷酸化的蛋白激酶Mζ(PKMζ)升高,但总PKMζ表达没增加。在STZ注射的大鼠ACC区微量注射PKMζ抑制剂ZIP可减弱谷氨酸能传递上调和疼痛行为表现。结论:1)随着糖尿病病程的延长,慢性并发症的发生率亦增加,但病程短、无糖尿病家族史、HDL降低及吸烟者更早发生慢性并发症,因此要提高健康体检意识,增加糖尿病及其慢性并发症的知晓率及诊治率,全民普及糖尿病教育知识,并对糖尿病危险因素要及时干预。2)根据抵抗素和脂联素水平可评估老年2型糖尿病的预后,并可对老年2型糖尿病患者心血管病的危险分层提供依据。3)在患糖尿病神经痛的啮齿动物中,它们的ACC神经元有中枢致敏作用,可能是糖尿病神经痛患者负面影响因素的基础。
[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.
【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R587.2

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