胰高血糖素样肽1受体激动剂Exendin-4复合骨髓源间充质干细胞输注促进STZ诱导的糖尿病大鼠胰岛功能重建的研究

发布时间：2018-03-04 17:12

本文选题：糖尿病　切入点：骨髓源间充质干细胞　出处：《中国人民解放军医学院》2015年博士论文　论文类型：学位论文

【摘要】：糖尿病已成为日益严重的人类公共健康问题。糖尿病的发病的关键是胰岛p细胞数量下降及功能受损。目前现有的传统糖尿病治疗手段如糖尿病口服药物及胰岛素等并不能完全恢复胰岛β细胞数量及其功能,不能阻止其并发症及病程进展。因而有必要研究新的治疗手段以促进胰岛β细胞数目恢复及功能重建,从而根本上治愈糖尿病。近年来,间充质干细胞(Mesenchymal stem cells, MSCs)因其所具有的无限增殖能力、多向分化潜能、分泌多种活化因子,调节微环境,活化内源性祖细胞等特性而被广泛应用于多种疾病如神经系统、创伤修复、心血管疾病等。大量动物及人体研究发现,MSCs输注治疗能有效改善糖尿病患者的高血糖,明显恢复胰腺β细胞数量及其功能,但其机制却尚未被完全阐明。目前已有的研究认为其可能的机制有：MSCs通过内分泌效应促进胰腺干细胞分化为胰岛β细胞；MSCs直接转分化为胰岛β细胞；MSCs促进导管细胞及其他胰岛细胞如α细胞转分化为胰岛β细胞。我们之前的研究发现在2型糖尿病中MSCs治疗能通过促进胰岛再生及减轻外周胰岛素抵抗而发挥其抗糖尿病作用,在1型糖尿病中MSCs很可能通过分泌效应而促进β细胞原位再生而发挥其抗糖尿病作用。然而这种胰岛内新生的β细胞功能并不成熟,具体表现在其血糖并不能完全恢复至正常水平。特别是在1型糖尿病中,MSCs治疗后空腹血糖能迅速恢复至正常水平,但餐后血糖并不能完全恢复。因而有必要寻找新的治疗方式以增强MSCs治疗效果,并促进新生的p细胞进一步功能成熟,以达到更好的治疗效果。近年来研究发现一种肠促胰素--胰高血糖素样肽1 (Glucagon-like peptide 1,G1p-1),能以葡萄糖依赖的模式刺激胰岛β细胞分泌胰岛素,抑制a细胞分泌胰高血糖素,刺激β细胞内胰岛素的合成,并能通过促进β细胞增殖,再生及抑制其凋亡对β细胞起保护作用。由于G1p-1半衰期极短,其长效类似物Exendin-4由于其相似的促胰岛素分泌及合成、β细胞保护及促再生作用而广泛引用。因而我们提出假设：如果将Exendin-4与MSCs复合治疗糖尿病能否促进胰岛β细胞的再生及其功能成熟?在本研究中,我们在链脲佐菌素(Strepozotocin, STZ)诱导的糖尿病大鼠模型中,分别给予同种异体的大鼠骨髓源间充质干细胞(Bone Marrow derived Mesenchymal Stem Cells, BM MSCs)输注和(或)Exendin-4治疗,观察胰岛β细胞的数量再生及其功能恢复情况。结果表明,Exendin-4与MSCs复合治疗能有效改善糖尿病大鼠的高血糖,促进胰岛内β细胞数量恢复及其功能成熟。其机制可能为MSCs促进胰岛内α细胞增生并向β细胞转分化从而促进β细胞数量恢复。Exendin-4则能进一步促进新生β细胞成熟相关标记物如PDX-1、MafA、GLP-1R, FoxOl等的表达,提高β细胞在葡萄糖刺激下的分泌胰岛素功能,从而促进其功能成熟。本研究为MSCs治疗糖尿病提供了新的理论支持,通过复合Exendin-4治疗能有效提高其促进胰岛再生的效率,将来有可能成为新的糖尿病治疗模式。
[Abstract]:Human diabetes has become a growing public health problem. The key to the pathogenesis of diabetes mellitus is the number of islet P cells decreased and impaired function. The traditional means of existing diabetes treatment such as diabetes oral drugs and insulin can not completely restore the number of islet beta cells and its function, can stop the progress of its complications and it is necessary to study the course of the disease. New treatments to promote islet beta cell number of recovery and functional reconstruction, thereby fundamentally cure diabetes. In recent years, mesenchymal stem cells (Mesenchymal stem cells, MSCs) because it has unlimited proliferation, differentiation, secretion of a variety of activating factor, regulating microenvironment, activation of endogenous progenitor cells and other characteristics is widely used in a variety of diseases such as nervous system, wound repair, cardiovascular disease and so on. A large number of animal and human studies found that MSCs infusion therapy Effectively improve the high blood glucose in diabetic patients, significantly restored the number and function of pancreatic beta cells, but the mechanism has not been fully elucidated. The present study considers its possible mechanisms: MSCs by endocrine effects promote pancreatic stem cells to differentiate into islet beta cells; MSCs direct transdifferentiation into islet beta cells; MSCs cells promote catheter and other islet cells such as alpha cells to differentiate into islet beta cells. Our previous study found in type 2 diabetes MSCs treatment can promote islet regeneration and reduce peripheral insulin resistance and exerts its anti diabetic effect in type 1 diabetes mellitus MSCs probably by secreting effect and promote beta cell regeneration and play the anti diabetic effect. However, the islet beta cell function in the newborn is not mature, the specific performance in their blood sugar and can not be completely restored to normal levels. Especially in the Type 1 diabetes, MSCs after treatment, fasting blood glucose can be quickly returned to normal levels, but the postprandial blood glucose can not be completely recovered. So it is necessary to find new treatment methods to enhance the curative effect of MSCs, and promote the new P cells further mature, in order to achieve better therapeutic effect. In recent years, the study found a sausage pancreatotrophin -- glucagon like peptide 1 (Glucagon-like peptide 1, G1p-1), can be in a Glucose dependent mode stimulate insulin secretion, inhibit a cell secretion of glucagon, insulin stimulates the synthesis of beta cells, and can promote beta cell proliferation, regeneration and apoptosis protection on the beta cells. Because of its short half-life of G1p-1, its long-acting analogues of Exendin-4 due to its similar insulin secretion and synthesis, beta cell protection and promotion and widely cited regeneration. So we put forward hypothesis: If the Exendin-4 and MSCs compound treatment of diabetes can promote the regeneration and function of islet beta cell maturation? In this study, we in streptozotocin (Strepozotocin, STZ) - induced diabetic rat model, rats were given allogeneic bone marrow derived mesenchymal stem cells (Bone Marrow derived Mesenchymal Stem Cells, BM, MSCs) and (or) Exendin-4 infusion therapy, observe the number of islet beta cell regeneration and functional recovery. The results showed that Exendin-4 and MSCs combined treatment can effectively improve hyperglycemia in diabetic rats, promote islet beta cell number and function recovery of mature. The possible mechanism is MSCs promote islet alpha and beta cell proliferation to cell transdifferentiation and promote beta cell number recovery.Exendin-4 can further promote the new beta cell maturation markers such as PDX-1, MafA, GLP-1R, and the expression of FoxOl,. The insulin secretion function of beta cells in high glucose stimulation, so as to promote the function of mature. This study provides a new theoretical support for the treatment of diabetes by MSCs, combined with Exendin-4 treatment can effectively improve the efficiency and promote islet regeneration, may become a new treatment mode of diabetes in the future.

【学位授予单位】：中国人民解放军医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R587.1

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