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）：该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，胃肠道外科手术在改善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。我们开发了一种新的T2DM大鼠模型，加州大学戴维斯分校T2DM （UCD-T2DM）大鼠，它比其他可用的模型更准确地模拟了临床人类T2DM的病理生理。IT手术模型很有趣，因为它分离了Roux-en-Y胃旁路术（RYGB）中发生的主要解剖改变之一，即IT手术将远端小肠近端移动，导致未完全消化的营养物质与远端小肠粘膜接触增加，导致肠道激素分泌增加，如胰高血糖素样肽-1 （GLP-1）和肽- yy （PYY）。相比之下，RYGB减少胃体积，绕过近端小肠，增加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，糖尿病发病年龄明显延迟（约3个月），循环活性GLP-1和PYY也有所增加。因此，我们建议进一步研究IT手术延缓糖尿病的潜在机制。这些研究可能有助于确定预防和治疗胰岛素抵抗和2型糖尿病的新的非手术方法。我们提出以下具体目标：1：验证糖尿病前期UCD-T2DM大鼠的IT手术通过影响GI激素（GLP-1、PYY和ghrelin）、脂肪细胞激素、脂联素的产生、分泌和信号传导，以及通过改变胆酸代谢和肠道菌群，延缓T2DM发病的假设。为此，将监测血糖并测量体内葡萄糖耐量和胰岛素敏感性的评估。每月测量循环脂质、激素和胆汁酸。将进行肠-脑轴不同水平的回肠和盲肠微生物谱和异位脂质沉积、胰岛形态和厌食和厌食激素受体基因表达的特异性组织分析。2：验证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，线粒体功能（氧摄取、ROS产生、线粒体偶联和钙运输）将在从几个组织（肝脏、骨骼肌、心脏和脂肪）中分离的线粒体中进行评估。IT组、假手术组和非手术对照组在术后1个月和3个月进行所有组织分析。