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

描述（由申请人提供）：本申请涉及广泛挑战领域（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（T2 DM）患病率的增加，需要新的糖尿病预防策略。我们开发了一种新型T2 DM大鼠模型，即加州大学戴维斯分校T2 DM（UCD-T2 DM）大鼠，并对其进行了表征，该模型比其他可用模型更准确地模拟了临床人类T2 DM的病理生理学。IT手术模型是令人感兴趣的，因为它隔离了Roux-en-Y胃旁路术（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，导致不太完全消化的营养物质与远端小肠粘膜的接触增加，从而导致肠道激素（如胰高血糖素样肽-1（GLP-1）和肽-YY（PYY））的分泌增加。相比之下，RYGB减少胃容量，绕过近端小肠，并增加营养物流向远端小肠。在我们目前的研究中，我们已经证明，与假手术动物相比，IT中葡萄糖耐量和胰岛素敏感性改善，糖尿病发病年龄显著（约3个月）延迟，以及循环活性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。这些研究可能有助于确定预防和治疗胰岛素抵抗和T2 DM的新的非手术方法。我们提出了以下具体目的：1：检验在糖尿病前期UCD-T2 DM大鼠中进行IT手术通过影响GI激素（GLP-1、PYY和ghrelin）和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汁酸代谢和肠道菌群来延迟T2 DM发作的假设。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、胰岛形态和肠-脑轴不同水平的促排泌和促食欲激素受体基因表达的特定组织分析。第二章：检验IT手术通过保留在T2 DM发生和进展期间恶化的线粒体功能来延迟糖尿病发作的假设。为此，将在从几种组织（肝脏、骨骼肌、心脏和脂肪）分离的线粒体中评价线粒体功能（氧摄取、ROS产生、线粒体偶联和钙转运）。在IT、假手术和非手术对照组中，将在术后1个月和3个月进行所有组织分析。 公共卫生相关性：减肥手术逆转T2 DM的临床观察为研究人员提供了一种新的工具，用于识别T2 DM的新预防和治疗选择。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，回肠间置手术显著延迟了我们实验室开发的新型大鼠模型（UCD-T2 DM大鼠）中T2 DM的发作，该模型比其他现有啮齿动物模型更准确地模拟临床人类T2 DM。因此，拟议研究的主要目标是研究回肠间置手术改善UCD-T2 DM大鼠胰岛素敏感性和葡萄糖耐量并延迟T2 DM发作的几种潜在机制。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贡献。

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.