In vivo effects of physical exercise on human islet structure and function

项目总结/摘要 缺乏身体活动是许多慢性疾病的主要原因。长期运动是一种预防工具，也是一种非预防工具 用于代谢紊乱如肥胖、胰岛素抵抗、前驱糖尿病和糖尿病的药物治疗。 运动对胰岛有直接和间接的影响。间接地，运动改善外周 葡萄糖摄取和胰岛素敏感性，减少人类和啮齿动物β细胞的代谢负荷。证据 从啮齿动物的研究认识到，运动直接改善β细胞增殖，存活，葡萄糖敏感， 胰岛素信号传导和胰岛素含量。在体外，人和啮齿动物肌管分泌的可溶性因子急性 并直接增强β细胞胰岛素分泌、增殖和存活。重要的是，急性和 长期运动的人类受试者保护β细胞免于烟碱介导的死亡。对人类来说， 改善β细胞功能，尽管更高的胰岛素敏感性。然而，运动对人体的确切影响 胰岛结构和功能还没有在体内确定，因为人类受试者中的胰岛是不可接近的。 因此，有必要将目前的体外研究转移到运动对人类胰岛的影响上。 将生物学转化为生理学我研究的长期目标是了解 运动会影响人体胰岛的结构和功能。我假设， 体育锻炼通过激活细胞内转录途径保护人类胰岛功能 增殖和存活以及促进胰岛血管功能。这一假设将在两个具体的 目标。具体目标1是确定体育锻炼对人类胰岛生物学的影响，具体目标2是确定体育锻炼对人类胰岛生物学的影响。 将体育锻炼作为胰岛移植的辅助治疗。我会用人体胰岛 移植到小鼠眼睛模型中，为克服主要障碍提供了技术解决方案 这阻碍了对运动对人体胰岛生物学的直接影响的识别。一个很大的优势是我可以 纵向监测人体胰岛结构和血管系统，以及评估胰岛和血管功能。我会 比较运动和静坐治疗的接受者移植相同的人胰岛制剂， 避免了与来自不同供体的人胰岛制备物相关的可变性。人胰岛 转录组和功能将在第一次运动后评估。在他们的成功完成，我的 研究将作为运动处方的基础，以保护胰岛功能和质量， 人胰岛移植的辅助治疗。

Project Summary/Abstract Physical inactivity is a primary cause of many chronic diseases. Chronic exercise is a prevention tool and a non- pharmacological treatment for metabolic disorders such as obesity, insulin resistance, prediabetes, and diabetes. Exercise has both direct and indirect effects impacting pancreatic islets. Indirectly, exercise improves peripheral glucose uptake and insulin sensitivity, reducing the metabolic load on human and rodent beta cells. Evidence from rodent studies appreciate that exercise directly improves beta cell proliferation, survival, glucose sensing, insulin signaling and insulin content. In vitro, soluble factors secreted by human and rodent myotubes acutely and directly potentiate beta cell insulin secretion, proliferation and survival. Importantly, serum of acute and chronic exercised human subjects protects beta cells from cytokine-mediated death. In humans, exercise improves beta cell function despite greater insulin sensitivity. However, the precise effects of exercise on human islet structure and function have not been determined in vivo because islets in human subjects are not accessible. Therefore, there is a need to move current in vitro studies addressing the effects of exercise on human islet biology into a more physiological setting. The long-term goal of my research is to understand how physical exercise impacts human pancreatic islet structure and function in the living organism. I hypothesize that regular physical exercise preserves human islet function by activating transcriptional pathways involved in cell proliferation and survival and by promoting islet vascular function. This hypothesis will be tested in two specific aims. Specific Aim 1 is to determine the impact of physical exercise on human islet biology and Specific Aim 2 will establish physical exercise as an adjuvant therapy for islet transplantation. I will use the human islet transplantation into the mouse eye model which offers a technological solution to overcome major roadblocks that prevent identifying the direct effects of exercise on human islet biology. A great advantage is that I can monitor longitudinally human islet structure and vasculature as well as assess islet and vascular functions. I will compare exercise- and sedentary-treated recipients transplanted with the same human islet preparation, thus circumventing the variability associated with human islet preparations from different donors. Human islet transcriptome and function will be assessed after exercise for the first time. At their successful completion, my studies will serve as the basis of exercise prescription for preservation of islet function and mass as well as an adjuvant therapy to human islet transplantation.