Mechanisms underlying exacerbation of inflammatory bowel disease by diabetes

糖尿病导致炎症性肠病恶化的机制

基本信息

批准号：
10597035
负责人：
Kendra Leigh Francis-Stream
金额：
$ 7.84万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10597035
关键词：
Acceleration Acids Address Adult Anti-Inflammatory Agents Antidiabetic Drugs Autopsy Biochemical Biological Assay Blood Glucose Body Weight decreased Chronic Clinical Colitis Colon Complications of Diabetes Mellitus Consumption Crohn&apos s disease Development Dextrans Diabetes Mellitus Diet Disease Disease Outcome Disease Progression Disease susceptibility Dose Epithelium Exposure to Extracellular Matrix Feces Fluorescein-5-isothiocyanate Foundations Functional disorder Gastroenterology Genetic Genetic Models Glucose Goals Hemorrhage Hepatology High Fat Diet Histologic Hospitalization Hyperglycemia Immune System Diseases Impairment Incidence Inflammation Inflammatory Inflammatory Bowel Diseases Intestines Knockout Mice Link Mass Spectrum Analysis Measures Medical Medical Care Costs Mesalamine Metformin Modeling Modernization Morbidity - disease rate Mucins Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Onset of illness Oral Outcome Outcome Study Pathogenicity Pathologic Pathology Patient-Focused Outcomes Patients Permeability Population Population Study Prevalence Process Production Proteins Rectum Research Research Priority Risk Risk Factors Rodent Severities Societies Sodium Sodium Dextran Sulfate Stains Streptozocin Structure of beta Cell of islet Symptoms Testing Tight Junctions Time Tissue Sample Toxin Translating Treatment Protocols Treatment outcome Ulcerative Colitis United States University resources Washington Wild Type Mouse Work comorbidity diabetes management diabetic diet-induced obesity disorder risk economic cost effective therapy glycemic control gut inflammation gut microbiome improved in vivo infection risk inhibitor insight interest intestinal barrier intestinal epithelium intestinal injury mortality mouse model multidisciplinary novel nutrition obese patients obesogenic polysulfated glycosaminoglycan pre-clinical prevent rectal skills symporter traditional therapy translational potential

项目摘要

Project Summary Type 2 diabetes (T2D) and inflammatory bowel disease (IBD) are among the most challenging and costly medical disorders of modern society. Both disease processes also share a common pathophysiology characterized by a chronic inflammatory state, altered gut microbiome, and dysfunctional intestinal barrier. Hyperglycemia is the primary cause of the many complications of diabetes, and recent studies have shown that hyperglycemia is capable of directly impairing intestinal barrier function independent of diet and obesity. Population-based studies have shown that patients with IBD also have an increased risk of T2D, which has important clinical consequences as comorbid T2D in patients with IBD is a predictor of poor disease-related outcomes, though the causative mechanisms remain unknown. In this proposal, we will investigate the novel hypothesis that diabetic hyperglycemia in the setting of diet-induced obesity (DIO) worsens IBD disease activity by increasing intestinal inflammation and associated barrier dysfunction. Specifically, we propose to characterize the effect of diabetic hyperglycemia on clinical and biochemical measures of intestinal inflammation and barrier function in murine models of IBD, and to determine the extent to which control of glycemia decreases intestinal inflammation and improves clinical outcomes in diabetic murine models of IBD. Diabetic-range hyperglycemia will be induced by administration of low-dose streptozotocin (STZ) in two independent models of IBD: 1) C57BL/6J wild-type (WT) mice treated with dextran sodium sulfate (DSS) and 2) Mdr1 knockout mice that spontaneously develop colitis, made obese by consumption of an obesogenic high-fat diet (HFD) or fed standard chow. The impact of hyperglycemia on intestinal barrier function and IBD pathology in the setting of DIO will be assessed using immunohistochemical staining, dextran-FITC permeability assays, and characterization of the components of the intestinal extracellular matrix. We will then investigate the translational potential of treating diabetic hyperglycemia to decrease IBD progression by administering a sodium-glucose cotransportor-2 (SGLT2) inhibitor to normalize glycemia in diabetic murine models of IBD. Lastly, SGLT2 inhibitors will be administered in combination with topical 5-aminosalysilic acids, which are standard first line therapy for mild-to-moderate ulcerative colitis but often fail to control more significant disease, to determine whether treating diabetic hyperglycemia improves the efficacy of introductory IBD therapies. The proposed project unites the clinical gastroenterology, hepatology and nutrition interests and research skills of the applicant as well as the considerable multi-disciplinary resources of the University of Washington Diabetes Institute to advance understanding of the mechanisms by which diabetic hyperglycemia influences intestinal inflammation, with the ultimate goal of understanding shared pathogenic mechanisms and identifying more effective treatments for both conditions.

项目摘要 2型糖尿病（T2D）和炎症性肠病（IBD）是最具挑战性和昂贵的医疗之一现代社会的疾病。这两种疾病过程也共享一种常见的病理生理学，其特征是慢性炎症状态，肠道微生物组改变和功能失调的肠屏障。高血糖是糖尿病许多并发症的主要原因，最近的研究表明高血糖是能够直接损害与饮食和肥胖无关的肠道屏障功能。基于人群的研究已经表明IBD患者的T2D风险也增加，这具有重要的临床后果由于IBD患者的合并症T2D是与疾病相关结果不佳的预测指标，尽管是病因机制仍然未知。在此提案中，我们将研究糖尿病的新假设在饮食诱导的肥胖症（DIO）的环境中高血糖通过增加肠道的IBD疾病活性恶化炎症和相关的屏障功能障碍。具体而言，我们建议表征糖尿病的影响关于鼠类肠炎和屏障功能的临床和生化测量高血糖 IBD的模型，并确定糖症的控制程度减少肠道炎症和改善IBD糖尿病鼠模型的临床结果。糖尿病范围高血糖将由在IBD的两个独立模型中给予低剂量链蛋白酶（STZ）：1）C57BL/6J野生型（WT）用硫酸钠（DSS）和2）MDR1敲除小鼠自发发展结肠炎的小鼠，通过消费肥胖的高脂饮食（HFD）或喂养标准食物来肥胖。的影响在DIO的情况下，将评估有关肠道屏障功能和IBD病理的高血糖免疫组织化学染色，葡萄晶型渗透性测定和成分的表征肠外基质基质。然后，我们将研究治疗糖尿病的翻译潜力高血糖通过施用钠 - 葡萄糖共转运2（SGLT2）来降低IBD的进展抑制剂在IBD的糖尿病鼠模型中归一化血糖。最后，SGLT2抑制剂将在与局部5-氨基甲硅酸酸的结合，这是标准的一线疗法，用于轻度至中度溃疡性结肠炎，但通常无法控制更重要的疾病，以确定是否治疗糖尿病高血糖提高了IBD疗法入门的功效。拟议的项目将临床团结起来申请人的胃肠病学，肝病学和营养兴趣和研究技能华盛顿大学糖尿病研究所的大量多学科资源了解糖尿病高血糖影响肠道炎症的机制，了解共同的致病机制并确定两者的更有效治疗的最终目标状况。