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: 8486429
• 负责人: Bethany Paige Cummings
• 金额: $ 32.32万
• 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/8486429
• 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（T2DM）患病率的增加，迫切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 UCD-T2DM 大鼠，它比其他现有的啮齿动物模型更准确地模拟人类 T2DM 的病理生理学。使用该大鼠模型，我们证明回肠介入 (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（相当于人类寿命的 10-15 年）。与人类临床研究类似，这种起效延迟与餐后 GLP-1 分泌和循环胆汁酸的增加有关。此外，VSG 手术的 UCD-T2DM 大鼠表现出循环胃饥饿素显着减少。所有这 3 种术后变化（GLP-1、胆汁酸和生长素释放肽）均被认为在改善减肥手术后血糖稳态方面发挥着作用，但之前尚未证明其中任何或所有这些变化是否有因果关系。评估这些机制（GLP-1、胆汁酸和生长素释放肽）中的每一种对 IT 和 VSG 手术后观察到的葡萄糖和脂质代谢改善的贡献，是了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：研究 GLP-1 增加、胆汁酸增加和 ghrelin 减少对 VSG 改善 UCD-T2DM 大鼠葡萄糖稳态和延缓糖尿病发病的作用的相对贡献。为此，将进行 3 项涉及添加和消除变化的研究。研究 1a 将包括：假手术、假手术 + 西他列汀、VSG、VSG + 毒蜥外泌肽 9-39。研究1b将包括：假手术、假手术+胆酸、VSG、VSG+顶端胆盐转运蛋白抑制剂。研究1c将包括：假手术、假手术+生长素释放肽拮抗剂、VSG、VSG+生长素释放肽替代。在所有体内葡萄糖稳态研究中，将评估β-细胞质量、内质网应激以及血浆、肝脏和肠道内容物胆汁酸谱。图 2：研究 GLP-1 和胆汁酸在 IT 手术改善 UCD-T2DM 大鼠葡萄糖稳态和延缓糖尿病发病的效果中的相对贡献。为此，将按照 SA1 中研究 1a 和研究 1b 的概述进行 2 项研究。图 3：检验 VSG 和 IT 手术相结合可预防 UCD-T2DM 大鼠糖尿病发作的假设。为此，将研究 6 个重量匹配组：sham-IT、sham-VSG、sham-IT/VSG、IT、VSG、IT/VSG。对动物进行跟踪直至糖尿病发作或长达 2 岁。将评估体内葡萄糖稳态，并在手术后 1.5 个月从一部分动物中取出组织，以评估 β 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谱。通过对通过激光捕获解剖从选定肠道片段中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群，将寻求新的治疗靶点。