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

体内体育锻炼对人体胰岛结构和功能的影响

基本信息

批准号：
10296007
负责人：
Joao Pedro Saar Werneck de Castro
金额：
$ 15.35万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10296007
关键词：
Acute Address Adjuvant Therapy Alpha Cell Anatomy Animal Model Anti-Inflammatory Agents Beta Cell Biology Blood Vessels Cell Proliferation Cell Survival Cell physiology Cessation of life Chronic Chronic Disease Clinical Contracts Diabetes Mellitus Diabetic mouse Endocrine Glands Engraftment Environment Exercise Experimental Designs Eye Fatty acid glycerol esters Genetic Transcription Glucagon Glucose Goals Graft Survival Growth Harvest Hormone secretion Human IL6 gene In Vitro Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Insulin-Like Growth Factor I Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Life Measures Mediating Metabolic Metabolic Diseases Modeling Monitor Mus Muscle Muscle Fibers Obesity Organism Oxidative Stress Pathway interactions Peripheral Physical Exercise Physiological Plasma Prediabetes syndrome Preparation Prevention Process Reading Recovery Research Rodent Running Serum Skeletal Muscle Streptozocin Structure Testing Time Transplant Recipients Transplantation Type 2 diabetic Vascular Endothelial Growth Factors Vascularization Workload anterior chamber cytokine diabetic diabetic patient exercise prescription exercise program exercise regimen glucose metabolism glucose uptake human model human subject improved in vivo insulin secretion insulin sensitivity insulin signaling islet male non-diabetic pancreatic islet function physical inactivity preservation prevent primary endpoint sedentary tool transcriptome transcriptome sequencing type I diabetic

项目摘要

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.

项目概要/摘要缺乏身体活动是许多慢性疾病的主要原因。长期锻炼是一种预防工具，也是一种非针对肥胖、胰岛素抵抗、糖尿病前期和糖尿病等代谢性疾病的药物治疗。运动对胰岛有直接和间接的影响。运动可以间接改善外周血管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。证据啮齿动物研究表明，运动可以直接改善 β 细胞增殖、存活、葡萄糖感应、胰岛素信号传导和胰岛素含量。体外，人类和啮齿动物肌管急性分泌可溶性因子并直接增强β细胞胰岛素分泌、增殖和存活。重要的是，急性和长期锻炼的人类受试者可以保护β细胞免受细胞因子介导的死亡。对于人类来说，运动尽管胰岛素敏感性更高，但仍可改善β细胞功能。然而，运动对人体的确切影响胰岛结构和功能尚未在体内确定，因为人类受试者中的胰岛是不可接近的。因此，有必要推动当前的体外研究，以解决运动对人类胰岛的影响生物学进入更生理的环境。我研究的长期目标是了解身体如何运动会影响生物体中的人体胰岛结构和功能。我假设定期体育锻炼通过激活细胞中涉及的转录途径来保护人类胰岛功能增殖和存活并促进胰岛血管功能。该假设将在两个特定的目标。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 将建立体育锻炼作为胰岛移植的辅助疗法。我将使用人类胰岛移植到小鼠眼睛模型中，这提供了克服主要障碍的技术解决方案妨碍确定运动对人类胰岛生物学的直接影响。一个很大的优点是我可以纵向监测人体胰岛结构和脉管系统，并评估胰岛和血管功能。我会比较移植相同人胰岛制剂的运动治疗和久坐治疗的受者，从而避免与不同捐赠者的人类胰岛制剂相关的变异性。人类胰岛转录组和功能将在第一次运动后进行评估。当他们成功完成时，我的研究将作为保护胰岛功能和质量的运动处方的基础，以及人胰岛移植的辅助治疗。