The effect of exercise on hepatic glucose metabolism in type 2 diabetes mellitus

运动对2型糖尿病肝脏糖代谢的影响

• 批准号: 8534863
• 负责人: Jason Winnick
• 金额: $ 11.28万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534863
• 关键词: Academia; Advisory Committees; Aerobic Exercise; Affect; American; Area; Blood Glucose; Body Weight decreased; Chronic; Clinical; Clinical Research; Clinical Treatment; Communities; Complex; Controlled Environment; Data; Development; Development Plans; Diabetes Mellitus; Doctor of Medicine; Doctor of Philosophy; Educational process of instructing; Etiology; Exercise; Exercise Physiology; Faculty; Fasting; Future; Gluconeogenesis; Glucose; Glucose Clamp Technique; Glucose Intolerance; Goals; Grant; Healthcare Systems; Hepatic; Hormones; Human; Hyperinsulinism; Institution; Insulin; Investigation; Knowledge; Lead; Light; Link; Liver; Measures; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolic Pathway; Methodology; Methods; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oral; Organ; Outcome; Patients; Phenotype; Physiological; Play; Population; Regulation; Research; Research Personnel; Research Project Grants; Role; Scientist; Skeletal Muscle; Students; TimeLine; Tissues; Training; Translational Research; Variant; Water; blood glucose regulation; career; career development; cost; disease characteristic; experience; fasting glucose; glucose metabolism; glucose production; glucose uptake; glycogenolysis; human subject; improved; instructor; insulin sensitivity; intrahepatic; liver function; member; research and development; research study; response; skills

DESCRIPTION (provided by applicant): I am a classically trained exercise physiologist, and the research aims of this proposal are to advance knowledge in the field on the link between exercise training and the regulation of hepatic glucose metabolism. Despite the fact that insulin's ability to regulate blood glucose homeostasis is impaired in people with type 2 diabetes mellitus (DM), and despite the well known effect of aerobic exercise training to improve hepatic insulin sensitivity, very little is known about how this improvement relates to the central role of the liver to take up glucose during the postprandial state and produce glucose during the fasted state. Instead, a lion's share of the research on exercise-induced increases in insulin sensitivity have focused on skeletal muscle. Because of the paucity of data in this area, I am proposing to focus my career on studying how aerobic exercise training improves the liver's ability to regulate blood glucose homeostasis in humans with DM. The combination of my clinical research experience as a Ph.D. student and my more recently developed expertise in liver glucose metabolism as a fellow and Instructor in Dr. Cherrington's lab make me uniquely suited to carry out the proposed studies. The broad aim of my experiments is to clarify how physiological outcomes related to hepatic glucose metabolism are improved in response to exercise-induced gains in hepatic insulin sensitivity in humans with DM. Specific aim #1 is to determine how aerobic exercise training, weight loss and their interaction improve splanchnic glucose uptake (SGU) in humans with DM. SGU will be measured using the oral glucose load-clamp method. This important question will be answered by comparing the rates of SGU before and after 12 weeks of exercise without weight loss, weight loss without exercise and aerobic exercise with weight loss, to SGU in non-exercise, non-weight loss controls. Aim #2 is to determine the intrahepatic metabolic pathway(s) that are responsible for the known reductions in hepatic glucose production (HGP) during the basal state and in response to physiological hyperinsulinemia. HGP will be measured using 3-3H glucose during isoglycemic-hyperinsulinemia, while gluconeogenesis and glycogenolysis will be measured using 2H2O. This question will be answered by comparing the rates of HGP, gluconeogenesis and glycogenolysis before and after 12 weeks of aerobic exercise plus weight loss to rates in non-exercise non-weight loss controls. Studies will be performed at Vanderbilt's clinical research center, a premier facility with all of the clinical expertise required to execute these studies in well controlled environment. In addition to the development of my research skills, I am also submitting a career development plan that includes additional coursework related to my future as a translational scientist, a plan to improve my teaching skills, attendance at professional development seminars, a research and career development mentoring committee made up of leaders in the field of diabetes-related research and a concise timeline outlining my career development. When completed, the training I will undergo will equip me with all of the skills necessary to become an independent academic faculty member at Vanderbilt or, if necessary, elsewhere. It is my ultimate goal to become a resourceful faculty member at a major academic institution and a capable leader of my own translational science lab that will serve the scientific community by linking exercise-induced improvements to hepatic insulin sensitivity with improved metabolic function of the liver in people with DM.

描述（由申请人提供）：我是一名受过经典训练的运动生理学家，本提案的研究目的是增进该领域关于运动训练与肝葡萄糖代谢调节之间联系的知识。尽管 2 型糖尿病 (DM) 患者的胰岛素调节血糖稳态的能力受到损害，并且有氧运动训练对改善肝脏胰岛素敏感性的作用众所周知，但人们对这种改善与胰岛素敏感性的关系知之甚少。的核心作用 肝脏在餐后状态吸收葡萄糖并在禁食状态产生葡萄糖。相反，大部分研究都是关于运动引起的胰岛素敏感性增加 重点关注骨骼肌。由于该领域的数据缺乏，我建议将我的职业重点放在研究有氧运动训练如何提高糖尿病患者肝脏调节血糖稳态的能力。结合我作为博士的临床研究经验。作为一名学生，以及我最近作为 Cherrington 博士实验室的研究员和讲师在肝脏葡萄糖代谢方面发展的专业知识，使我非常适合开展拟议的研究。我的实验的主要目的是阐明如何改善与肝脏葡萄糖代谢相关的生理结果，以响应运动引起的糖尿病患者肝脏胰岛素敏感性的提高。具体目标#1是确定有氧运动训练、减肥及其相互作用如何改善糖尿病患者的内脏葡萄糖摄取（SGU）。 SGU 将使用口服葡萄糖负载钳法进行测量。这个重要问题将通过比较 12 周不减肥运动、不运动减肥和有氧运动减肥前后的 SGU 率与不运动、非减肥对照的 SGU 率来回答。目标#2是确定肝内代谢途径，这些途径导致基础状态期间已知的肝葡萄糖生成（HGP）减少以及对生理性高胰岛素血症的反应。在等血糖高胰岛素血症期间，HGP 将使用 3-3H 葡萄糖进行测量，而糖异生和糖原分解将使用 2H2O 进行测量。这个问题将通过比较 12 周有氧运动加减肥前后的 HGP、糖异生和糖原分解率与不运动非减肥对照组的比率来回答。研究将在范德比尔特的临床研究中心进行，该中心是一个一流的设施，拥有在良好控制的环境中执行这些研究所需的所有临床专业知识。除了发展我的研究技能之外，我还提交了一份职业发展计划，其中包括与我作为转化科学家的未来相关的额外课程、提高我的教学技能的计划、参加专业发展研讨会、研究和职业发展由糖尿病相关研究领域的领导者组成的指导委员会和概述我职业发展的简明时间表。完成后，我将接受的培训将使我具备成为范德比尔特大学或其他地方（如有必要）的独立学术教员所需的所有技能。我的最终目标是成为主要学术机构的一名足智多谋的教员，并成为我自己的转化科学实验室的一位有能力的领导者，该实验室将为科学界服务。 通过将运动引起的肝脏胰岛素敏感性改善与糖尿病患者肝脏代谢功能的改善联系起来。