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（由适用提供）：迫切需要预防糖尿病的新策略，随着2型糖尿病（T2DM）的患病率增加。我们已经开发并表征了T2DM的新型大鼠模型，即UCD-T2DM大鼠，它比其他可用的啮齿动物模型更准确地模拟了人类T2DM的病理生理学。使用此大鼠模型，我们证明了回肠介入（IT）和垂直套筒口切除术（VSG）将糖尿病的发作降低了4-6个月（相当于人类的寿命为10 - 15年）。与人类临床研究类似，这种发作的延迟与餐后GLP-1分泌和循环胆汁酸的增加有关。此外，VSG操作的UCD-T2DM大鼠暴露于循环发芽肽的显着下降。所有这三种术后变化（GLP-1，胆汁酸和生长素蛋白）都被认为在减肥手术后的葡萄糖稳态改善中发挥作用，但是先前尚未证明任何或全部这些变化。评估这些机制（GLP-1，胆汁酸和生长素蛋白）对观察到的改善葡萄糖和脂质代谢后的贡献（VSG手术和VSG手术后观察到的改善）是理解负责疗法后观察到的代谢改善的机制的必要步骤。因此，我们提出以下特定目的：1：研究增加GLP-1，增加胆汁酸和减少生长素对VSG的影响的相对贡献，以改善UCD-T2DM大鼠中葡萄糖稳态并延迟糖尿病的发作。为此，将进行3项涉及加法和消融变化的研究。研究1a将包括：假，假， + sitagliptin，VSG，VSG + Exendin 9-39。研究1b将包括：假，假 +胆酸，VSG，VSG +顶胆汁盐转运蛋白抑制剂。研究1C将包括：假，假， +生长素蛋白拮抗剂，VSG，VSG +生长素蛋白替代。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，肝脏和肠含量胆汁酸谱。 2：研究GLP-1和胆汁酸在IT手术作用中的相对贡献，以改善UCD-T2DM大鼠的葡萄糖稳态和延迟糖尿病发作。为此，将对研究1A进行2项研究，并在SA1中进行研究1B。 3：为了检验VSG和IT手术组合的假设将防止UCD-T2DM大鼠糖尿病的发作。为此，将研究6个重量匹配的组：sham-it，sham-vsg，sham-it/vsg，it，vsg，it/vsg。这些动物将被遵循，直到糖尿病发作或最高2岁。将评估体内葡萄糖体内稳态，并在手术后1.5个月从动物的一部分中评估组织，以评估血浆，肝脏和肠含量的血浆，ER应激和胆汁酸轮廓。通过对通过激光捕获术中分离出的肠道内分泌细胞进行微阵列分析，将追求新的治疗靶标，并通过焦磷酸测序分析肠道微生物种群。

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.