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: 8343971
• 负责人: Bethany Paige Cummings
• 金额: $ 35万
• 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/8343971
• 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; 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. PUBLIC HEALTH RELEVANCE: Bariatric surgery is an effective therapeutic and preventative strategy for type 2 diabetes (T2DM), but the mechanisms responsible for this remain undefined. We propose to investigate the relative contributions of popularly cited post-operative changes of circulating hormones and metabolites to the metabolic improvements observed after bariatric surgery using a novel rodent model of T2DM. Furthermore, the hypothesis that ileal interposition and vertical sleeve gastrectomy in combination will prevent diabetes onset will be tested.

描述（由申请人提供）：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。我们开发并表征了一种新型T2 DM大鼠模型，即UCD-T2 DM大鼠，其比其他现有啮齿动物模型更准确地模拟了人类T2 DM的病理生理学。使用该大鼠模型，我们已经证明回肠间置术（IT）和垂直袖状胃切除术（VSG）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，这种发作延迟与餐后GLP-1分泌和循环胆汁酸的增加有关。此外，VSG操作的UCD-T2 DM大鼠表现出循环ghrelin的显著降低。所有这3种术后变化（GLP-1、胆汁酸和生长激素释放肽）均被认为在减肥手术后葡萄糖稳态改善中发挥作用，然而，先前尚未证明这些变化中的任何或全部是否存在因果关系。评价这些机制（GLP-1、胆汁酸和生长激素释放肽）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理解减肥手术后观察到的代谢改善机制的必要步骤。因此，我们提出了以下具体目标：1：研究GLP-1增加、胆汁酸增加和ghrelin减少对VSG改善UCD-T2 DM大鼠葡萄糖稳态和延迟糖尿病发作的作用的相对贡献。为此，将进行3项涉及增加和消融变更的研究。研究1a将包括：假手术、假手术+西格列汀、VSG、VSG + exendin 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。在所有研究中，将评估体内葡萄糖稳态、细胞质量、内质网应激和血浆、肝脏和肠内容物胆汁酸谱。第二章：研究GLP-1和胆汁酸在IT手术改善UCD-T2 DM大鼠葡萄糖稳态和延迟糖尿病发作的作用中的相对贡献。为此，将按照SA 1中研究1a和研究1b的概述进行2项研究。3：验证VSG和IT手术联合应用可预防UCD-T2 DM大鼠糖尿病发作的假设。为此，将研究6个体重匹配组：假手术-IT、假手术-VSG、假手术-IT/VSG、IT、VSG、IT/VSG。将对动物进行随访，直至糖尿病发作或2岁。将评估体内葡萄糖稳态，并在手术后1.5个月从动物亚组中采集组织，以评估血浆、肝脏和肠内容物的细胞质量、ER应激和胆汁酸谱。新的治疗靶点将通过对通过激光捕获解剖从选定的肠段分离的肠内分泌细胞进行微阵列分析和通过焦磷酸测序分析肠微生物种群来实现。 公共卫生关系：减肥手术是2型糖尿病（T2 DM）的有效治疗和预防策略，但其机制仍不明确。我们建议使用新型T2 DM啮齿动物模型研究广泛引用的术后循环激素和代谢物变化对减肥手术后观察到的代谢改善的相对贡献。此外，回肠间置术和垂直袖状胃切除术相结合将预防糖尿病发作的假设将被检验。