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

基本信息

批准号：
8901149
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901149
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

项目摘要

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，该模型更多。与其他现有的啮齿动物模型相比，我们能够准确地模拟人类 T2DM 的病理生理学，我们已经证明回肠介入 (IT) 和垂直袖状胃切除术 (VSG) 可以延缓糖尿病的发病。与人类临床研究类似，这种发病延迟与餐后 GLP-1 分泌和循环胆汁酸的增加有关。 T2DM 大鼠表现出循环胃饥饿素显着降低，所有这 3 种术后变化（GLP-1、胆汁酸和胃饥饿素）都被认为在改善血糖方面发挥作用。减肥手术后的体内平衡，然而，先前尚未证明这些变化中的任何一个或所有变化是否有因果关系。 IT 和 VSG 手术后的代谢是了解减肥手术后观察到的代谢改善机制的必要步骤，因此，我们提出以下具体目标： 1：研究 GLP-1 增加、胆汁酸增加的相对贡献。减少和胃饥饿素对 VSG 改善 UCD-T2DM 大鼠葡萄糖稳态和延迟糖尿病发作的作用为此，将进行 3 项研究的添加和消除，研究 1a 将包括：假手术、假手术 + 西格列汀、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。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。评估 2：研究 GLP-1 和胆汁酸在 IT 手术改善 UCD-T2DM 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 中的研究 1a 和研究 1b 进行 2 项研究：检验 VSG 和 IT 手术联合使用可预防 UCD-T2DM 大鼠糖尿病发作的假设。 -将研究匹配组：假-IT、假-VSG、假-IT/VSG、IT、VSG、IT/VSG 将跟踪动物直至糖尿病发作或最多2次。将评估体内葡萄糖稳态，并在手术后 1.5 个月从一部分动物身上采集组织，以评估血浆、肝脏和肠道内容物的 β 细胞质量、内质网应激和胆汁酸谱。通过对通过激光捕获解剖从选定的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来实现。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mesenteric arterial dysfunction in the UC Davis Type 2 Diabetes Mellitus rat model is dependent on pre-diabetic versus diabetic status and is sexually dimorphic.

DOI：
10.1016/j.ejphar.2020.173089
发表时间：
2020-04
期刊：
European journal of pharmacology
影响因子：
5
作者：
Sonali S. Shaligram;Farjana Akther;M. Razan;J. Graham;N. Roglans;M. Alegret;Arta Gharib Parsa;K. Stanhope;P. Havel;R. Rahimian
通讯作者：
Sonali S. Shaligram;Farjana Akther;M. Razan;J. Graham;N. Roglans;M. Alegret;Arta Gharib Parsa;K. Stanhope;P. Havel;R. Rahimian

Potentiation of Acetylcholine-Induced Relaxation of Aorta in Male UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rats: Sex-Specific Responses.

DOI：
10.3389/fphys.2021.616317
发表时间：
2021
期刊：
Frontiers in physiology
影响因子：
4
作者：
Akther F;Razan MR;Shaligram S;Graham JL;Stanhope KL;Allen KN;Vázquez-Medina JP;Havel PJ;Rahimian R
通讯作者：
Rahimian R

Adropin and insulin resistance: Integration of endocrine, circadian, and stress signals regulating glucose metabolism.