Dissecting mechanisms by which GI surgery delays diabetes onset in UCD-T2DM rats

剖析胃肠道手术延迟 UCD-T2DM 大鼠糖尿病发病的机制

• 批准号: 8662771
• 负责人: Bethany Paige Cummings
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662771
• 关键词: 2 year old; Ablation; Address; Adult; Animals; Apical; Bile Acids; Body Weight decreased; Cells; Cholic Acids; Clinical Research; Combined Modality Therapy; Defect; Deposition; Development; Diabetes Mellitus; Diabetes prevention; Dissection; Distal; Energy Metabolism; Enteroendocrine Cell; Epidemic; Evaluation; Excision; Exhibits; Functional disorder; Gastrectomy; Glucose; Goals; Greater curvature of stomach; Hormones; Human; Hyperglycemia; Impairment; Individual; Insulin; Insulin Resistance; Intestinal Content; Intestines; Investigation; Lasers; Length; Leptin; Lipids; Liver; Longevity; Matched Group; Mediating; Metabolic; Microarray Analysis; Modeling; Morbidity - disease rate; Morphology; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Plasma; Play; Population; Postoperative Period; Prevalence; Prevention; Production; Rattus; Relative (related person); Rodent; Rodent Model; Role; Signal Transduction; Small Intestines; Stress; Surgical Models; Testing; Therapeutic; Tissues; Weight; Work; bariatric surgery; bile salts; blood glucose regulation; endoplasmic reticulum stress; ghrelin; glucagon-like peptide 1; glucose disposal; glucose metabolism; improved; in vivo; inhibitor/antagonist; insulin secretion; insulin sensitivity; interest; islet; jejunum; lipid metabolism; microbial; new therapeutic target; novel; obesity treatment; prevent; pyrosequencing; receptor

DESCRIPTION (provided by applicant): With the increased prevalence of type-2 diabetes mellitus (T2DM), new strategies for diabetes prevention are urgently needed. We have developed and characterized a novel rat model of T2DM, the UCD-T2DM rat, which more accurately models the pathophysiology of T2DM in humans than other available rodent models. Using this rat model we have demonstrated that ileal interposition (IT) and vertical sleeve gastrectomy (VSG) delay the onset of diabetes by 4-6 months (equivalent to 10-15 years in a human lifespan). Similar to human clinical studies, this delay in onset is associated with increases of postprandial GLP-1 secretion and circulating bile acids. Furthermore, VSG-operated UCD-T2DM rats exhibit significant decreases of circulating ghrelin. All 3 of these post-operative changes (GLP-1, bile acids and ghrelin) have been suggested to play a role in the improvement of glucose homeostasis after bariatric surgery, however whether any or all of these changes are causally involved has not been previously demonstrated. Evaluation of the contribution of each one of these mechanisms (GLP-1, bile acids and ghrelin) to the observed improvements of glucose and lipid metabolism after IT and VSG surgery is a necessary step in understanding the mechanisms responsible for the metabolic improvements observed after bariatric surgery. Thus, we are proposing the following specific aims: 1: To investigate the relative contribution of increased GLP-1, increased bile acids and decreased ghrelin to the effect of VSG to improve glucose homeostasis and delay diabetes onset in UCD-T2DM rats. To this end, 3 studies involving addition and ablation of the change will be performed. Study 1a will include: sham, sham + sitagliptin, VSG, VSG + exendin 9-39. Study 1b will include: sham, sham + cholic acid, VSG, VSG + apical bile salt transporter inhibitor. Study 1c will include: sham, sham + ghrelin antagonist, VSG, VSG + ghrelin replacement. In all studies in vivo glucose homeostasis, ¿-cell mass, endoplasmic reticulum stress and plasma, liver and intestinal content bile acid profiles will be assessed. 2: To investigate the relative contribution of GLP-1 and bile acids in the effect of IT surgery to improve glucose homeostasis and delay diabetes onset in UCD-T2DM rats. To this end, 2 studies will be performed as outlined for Study 1a and Study 1b in SA1. 3: To test the hypothesis that VSG and IT surgery in combination will prevent the onset of diabetes in UCD-T2DM rats. To this end, 6 weight-matched groups will be studied: sham-IT, sham-VSG, sham-IT/VSG, IT, VSG, IT/VSG. The animals will be followed until diabetes onset or up to 2 years of age. In vivo glucose homeostasis will be assessed and tissues taken from a subset of animals at 1.5 months after surgery for assessment of ¿-cell mass, ER stress and bile acid profiles of plasma, liver and intestinal contents. New therapeutic targets will be pursued by performing microarray analysis of enteroendocrine cells isolated via laser capture dissection from selected gut segments and analyzing gut microbial populations by pyrosequencing.

描述(申请人提供)：随着2型糖尿病(T2 DM)患病率的增加，迫切需要新的糖尿病预防策略。我们开发了一种新的T2 DM大鼠模型，UCD-T2 DM大鼠，它比其他现有的啮齿动物模型更准确地模拟人类T2 DM的病理生理学。在这个大鼠模型上，我们证明了回肠间置(IT)和垂直袖状胃切除术(VSG)可将糖尿病的发病延迟4-6个月(相当于人的寿命为10-15年)。与人类临床研究相似，这种发病延迟与餐后GLP-1分泌和循环胆汁酸增加有关。此外，VSG组UCD-T2 DM大鼠外周血Ghrelin水平显著降低。所有这些术后的变化(GLP-1、胆汁酸和Ghrelin)都被认为在改善减肥手术后的血糖稳态方面发挥了作用，然而这些变化中的任何一个或所有这些变化是否都是因果关系尚未得到证实。评估每一种机制(GLP-1、胆汁酸和Ghrelin)对IT和VSG术后观察到的糖脂代谢改善的贡献是理解减肥手术后观察到的代谢改善的机制的必要步骤。因此，我们提出以下具体目标：1.探讨GLP-1升高、胆汁酸升高、Ghrelin降低在VSG改善UCD-T2 DM大鼠血糖稳态、延缓糖尿病发病中的作用。为此，将进行3项涉及添加和消融改变的研究。研究1a包括：假手术、假手术+西格列汀、血管紧张素转换酶、血管紧张素转换酶+exendin 9-39。研究1b将包括：假手术、假手术+胆酸、VSG、VSG+心尖胆盐转运蛋白抑制剂。研究1c将包括：假手术、假手术+Ghrelin拮抗剂、VSG、VSG+Ghrelin替代。在体内的所有研究中，将评估葡萄糖稳态、细胞质量、内质网压力以及血浆、肝脏和肠道内容物胆汁酸的变化情况。2：探讨GLP-1和胆汁酸在IT手术改善UCD-T2 DM大鼠血糖稳态、延缓糖尿病发病中的相对作用。为此，将按照SA1中研究报告1a和研究报告1b的概述进行2项研究。3：验证VSG和IT手术联合应用预防UCD-T2 DM大鼠糖尿病发病的假说。为此，将研究6个权重匹配的组：Sham-IT、Sham-VSG、Sham-IT/VSG、IT、VSG、IT/VSG。这些动物将被跟踪，直到糖尿病发作或最大2岁。在体内，将评估血糖稳态，并在手术后1.5个月从一组动物身上提取组织，以评估细胞质量、内质网应激以及血浆、肝脏和肠道内容物的胆汁酸分布。新的治疗目标将通过对通过激光捕获解剖从选定的肠段分离出的肠内分泌细胞进行微阵列分析，并通过焦磷酸测序分析肠道微生物种群来实现。