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）：本申请涉及广泛的挑战领域 (15)：转化科学和具体挑战主题，15-DK-111，胃肠道手术在改善 2 型糖尿病中的作用。随着 2 型糖尿病 (T2DM) 患病率的增加，需要新的糖尿病预防策略。我们开发并表征了一种新型 T2DM 大鼠模型，即加州大学戴维斯分校 T2DM (UCD-T2DM) 大鼠，它比其他可用模型更准确地模拟临床人类 T2DM 的病理生理学。 IT 手术模型很有趣，因为它隔离了 Roux-en-Y 胃绕道手术 (RYGB) 中进行的主要解剖学改变之一，即 IT 手术将远端小肠向近端移动，导致未完全消化的营养物质与胃的接触增加。远端小肠粘膜导致胰高血糖素样肽-1 (GLP-1) 和肽-YY (PYY) 等肠道激素分泌增加。相比之下，RYGB 减少了胃容量，绕过近端小肠并增加了远端小肠的营养通量。在我们目前的研究中，我们已经证明，与假手术动物相比，IT 患者的葡萄糖耐量和胰岛素敏感性得到改善，糖尿病发病年龄显着延迟（约 3 个月），并且循环活性 GLP-1 和 PYY 增加。因此，我们建议进一步研究 IT 手术延迟糖尿病的潜在机制。此类研究可能有助于确定预防和治疗胰岛素抵抗和 T2DM 的新非手术方法。我们提出以下具体目标： 1：检验糖尿病前期 UCD-T2DM 大鼠的 IT 手术通过影响胃肠道激素（GLP-1、PYY 和胃饥饿素）和脂肪细胞激素脂联素，并通过改变胆汁酸代谢和肠道微生物区系。为此，将监测血糖并测量葡萄糖耐量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。将进行回肠和盲肠微生物分析以及异位脂质沉积、胰岛形态以及肠-脑轴不同水平的促食欲和促食欲激素受体基因表达的特定组织分析。图 2：检验 IT 手术通过保留在 T2DM 发生和进展过程中恶化的线粒体功能来延缓糖尿病发病的假设。为此，将在从多种组织（肝脏、骨骼肌、心脏和脂肪）分离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 IT 组、假手术组和非手术对照组术后 1 个月和 3 个月进行。 公众健康相关性：减肥手术逆转 T2DM 的临床观察为研究人员提供了一种新工具，用于确定 T2DM 的新预防和治疗方案。因此，迫切需要开发和利用动物模型来研究减肥手术改善糖尿病的机制。我们实验室的最新结果表明，在我们实验室开发的新型大鼠模型 UCD-T2DM 大鼠中，回肠介入手术显着延迟了 T2DM 的发病，该模型比其他可用的啮齿动物模型更准确地模拟临床人类 T2DM。因此，本研究的主要目标是研究回肠介入手术改善 UCD-T2DM 大鼠胰岛素敏感性和葡萄糖耐量并延缓 T2DM 发病的几种潜在机制。将评估胃肠道和脂肪细胞激素产生的变化、胆汁酸和肠道微生物组成的变化以及线粒体功能的影响。