Surgical amelioration of type 2 diabetes: Hormones, microbiota and mitochondria

2 型糖尿病的手术改善：激素、微生物群和线粒体

• 批准号: 7830450
• 负责人: CECILIA GIULIVI
• 金额: $ 48.74万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7830450
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Age; Anatomy; Animal Model; Animals; Area; Bariatrics; Bile Acids; Blood Glucose; Body Weight decreased; Brain; Bypass; Calcium; California; Cell physiology; Clinical; Control Groups; Coupling; Deposition; Development; Diabetes Mellitus; Diabetes prevention; Distal; Down-Regulation; Endocrine; Exhibits; Functional disorder; Gastric Bypass; Gastrointestinal Hormones; Gastrointestinal Surgical Procedures; Gene Expression; Genes; Glucose; Goals; Heart; Hormone Receptor; Hormones; Human; Impairment; Individual; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intestines; Kidney; Laboratories; Length; Lipids; Liver; Measurement; Measures; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Monitor; Morphology; Mucous Membrane; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Oxygen; Pancreas; Peptide YY; Play; Prevalence; Prevention; Prevention approach; Production; Rattus; Receptor Gene; Reporting; Research Personnel; Resolution; Rodent Model; Role; Signal Transduction; Skeletal Muscle; Small Intestines; Stomach; Streptozocin; Surgical Models; Testing; Therapeutic; Tissues; Translational Research; Universities; Work; adiponectin; bariatric surgery; blood glucose regulation; diabetic; gastrointestinal; ghrelin; glucagon-like peptide 1; glucose tolerance; gut microflora; ileum; improved; in vivo; insulin secretion; insulin sensitivity; insulin signaling; interest; islet; microbial; mitochondrial dysfunction; novel; obesity treatment; public health relevance; therapeutic target; tool; uptake

DESCRIPTION (provided by applicant): This application addresses the Broad Challenge Area (15): Translational Science and specific Challenge Topic, 15-DK-111, the role of gastrointestinal surgical procedures in amelioration of type 2 diabetes. With the increased prevalence to type-2 diabetes mellitus (T2DM), new strategies for diabetes prevention are needed. We have developed and characterized a novel rat model of T2DM, the University of California, Davis T2DM (UCD-T2DM) rat, which more accurately models the pathophysiology of clinical human T2DM than other available models. The IT surgical model is of interest because it isolates one of the major anatomic alterations performed in Roux-en-Y gastric bypass (RYGB), namely IT surgery moves the distal small intestine proximally, resulting in increased contact of less completely digested nutrients with the mucosa of the distal small intestine resulting in increased secretion of gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide-YY (PYY). In comparison, RYGB reduces gastric volume, bypasses the proximal small intestine and increases the nutrient flux to the distal small intestine. In our current studies, we have demonstrated improved glucose tolerance and insulin sensitivity and a significant (~3 month) delay in the age of diabetes onset in IT compared with sham-operated animals, as well as increases of circulating active GLP-1 and PYY. Thus, we are proposing to further investigate potential mechanisms by which IT surgery delays diabetes. Such studies are likely to help identify new non-surgical approaches for the prevention and treatment of insulin resistance and T2DM. We are proposing the following Specific Aims: 1: To test the hypothesis that IT surgery in pre-diabetic UCD-T2DM rats delays the onset of T2DM by influencing the production, secretion, and signaling of GI hormones (GLP-1, PYY, and ghrelin), and the adipocyte hormone, adiponectin and by altering bile acid metabolism and intestinal microflora. To this end, blood glucose will be monitored and in vivo assessment of glucose tolerance and insulin sensitivity will be measured. Monthly measurements of circulating lipids, hormones and bile acids will be taken. Ileal and cecal microbial profiling and specific tissue analysis of ectopic lipid deposition, islet morphology and anorexegenic and orexegenic hormone receptor gene expression at different levels of the gut-brain axis will be performed. 2: To test the hypothesis that IT surgery delays the onset of diabetes by preserving mitochondrial function which deteriorates during the development and progression of T2DM. To this end, mitochondrial function (oxygen uptake, ROS production, mitochondrial coupling, and calcium transport) will be evaluated in mitochondria isolated from several tissues (liver, skeletal muscle, heart, and adipose). All tissue analyses will be performed at 1 and 3 months after surgery in IT, Sham and non-surgical control groups. PUBLIC HEALTH RELEVANCE: The clinical observation that bariatric surgery reverses T2DM provides researchers with a new tool for the identification of new prevention and treatment options for T2DM. Thus, the development and utilization of animal models for investigating the mechanisms by which bariatric surgical procedures ameliorate diabetes are urgently needed. Recent results from our laboratory have demonstrated that ileal interposition surgery significantly delays T2DM onset in a novel rat model developed in our laboratory, the UCD-T2DM rat, which more accurately models clinical human T2DM than other available rodent models. Thus, the major goal of the proposed study is to investigate several potential mechanisms by which ileal interposition surgery improves insulin sensitivity and glucose tolerance and delays the onset of T2DM in UCD-T2DM rats. The contributions of alterations in the production of gastrointestinal and adipocyte hormones, changes of bile acids and intestinal microbial composition, as well as mitochondrial function will be assessed.

描述（由申请人提供）：此申请涉及广泛的挑战领域（15）：转化科学和特定挑战主题，15-DK-111，胃肠道手术程序在改善2型糖尿病中的作用。随着2型糖尿病（T2DM）的患病率增加，需要进行预防糖尿病的新策略。我们已经开发并表征了T2DM的新型大鼠模型，加利福尼亚大学Davis T2DM（UCD-T2DM）大鼠，它比其他可用模型更准确地模拟了临床人类T2DM的病理生理学。 IT手术模型引起了人们的关注，因为它隔离了在roux-en-y胃旁路（RYGB）中进行的主要解剖变化之一（RYGB），即手术在近端移动远端小肠，从而导致不太完全消化的养分与远端小肠所产生的乳腺素含量增加，从而增加了完全消化的养分。 （GLP-1）和肽-YY（PYY）。相比之下，RYGB减少了胃体积，绕过近端小肠，并将营养通量增加到远端小肠。在我们目前的研究中，与假手术动物相比，我们已经证明了糖尿病发作年龄的葡萄糖耐受性和胰岛素敏感性的提高，并且显着（约3个月）的延迟，以及循环活跃的GLP-1和PYY的增加。因此，我们提议进一步研究IT手术延迟糖尿病的潜在机制。这些研究可能有助于确定用于预防和治疗胰岛素抵抗和T2DM的新的非手术方法。我们提出以下具体目的：1：测试以下假说：糖尿病前UCD-T2DM大鼠手术通过影响GI激素（GLP-1，Pyy和Ghrelin）的生产，分泌和信号传导，延迟T2DM的发作，以及通过脂肪素，脂肪素，脂肪素和脂肪素酸，并拟合脂肪素酸含量。为此，将监测血糖，并测量葡萄糖耐受性和胰岛素敏感性的体内评估。每月测量循环脂质，激素和胆汁酸。卵形和盲肠微生物分析以及特定的组织脂质沉积，胰岛形态，厌食和甲状腺素激素受体基因表达将在不同水平的肠道轴轴上进行。 2：测试以下假设：IT手术通过保留线粒体功能延迟糖尿病的发作，该功能在T2DM的发展和进展过程中恶化。为此，将在从几个组织（肝脏，骨骼肌，心脏和脂肪）中分离出的线粒体中评估线粒体功能（氧摄取，ROS产生，线粒体偶联和钙转运）。所有组织分析将在手术后1和3个月（假手术和非手术对照组）进行。 公共卫生相关性：临床观察结果，即减肥手术逆转T2DM为研究人员提供了一种新的工具，用于鉴定T2DM的新预防和治疗选择。因此，迫切需要减肥手术程序改善糖尿病的动物模型的开发和利用。我们实验室的最新结果表明，回肠介入手术在我们的实验室中开发的新大鼠模型UCD-T2DM大鼠中显着延迟了T2DM发作，该模型与其他可用的啮齿动物模型相比，它更准确地模拟了临床人类T2DM。因此，拟议的研究的主要目的是研究多种潜在的机制，通过这些机制，回肠介入手术可以提高胰岛素敏感性和葡萄糖耐受性，并延迟UCD-T2DM大鼠中T2DM的发作。将评估胃肠道和脂肪细胞激素，胆汁酸和肠道微生物组成的变化以及线粒体功能的改变的贡献。