Immunometabolic impact of stress hyperglycemia on tuberculosis treatment outcomes and risk of diabetes mellitus

应激性高血糖对结核病治疗结果和糖尿病风险的免疫代谢影响

• 批准号: 10576860
• 负责人: Matthew James Magee
• 金额: $ 72.67万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-04 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576860
• 关键词: Address; Adipose tissue; Anthropometry; Anti-Inflammatory Agents; Biological Markers; Biopsy; Caring; Cause of Death; Cessation of life; Chronic; Clinical; Collaborations; Communicable Diseases; Country; Data; Diabetes Mellitus; Diagnosis; Disease; Endocrinology; Enrollment; Epidemic; Epidemiology; Event; Future; Glucose; Glucose Intolerance; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Health; Homeostasis; Human; Hyperglycemia; Hypertrophy; Immune; Immunology; Incidence; Individual; Infection; Inflammation; Inflammatory; Insulin; Insulin Resistance; Integration Host Factors; Intervention Studies; Lipids; Lung diseases; Measures; Metabolic; Metabolic Diseases; Metabolism; Modeling; Obesity; Operative Surgical Procedures; Outcome; Participant; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Physiological; Plasma; Public Health; Pulmonary Tuberculosis; Recommendation; Regulation; Relapse; Reporting; Research; Research Personnel; Resolution; Retrospective Studies; Risk; Risk Reduction; Sputum; Stress; Subcutaneous Tissue; T-Cell Activation; Time; Tissues; Trauma; Treatment outcome; Tuberculosis; Tuberculosis diagnosis; Uncertainty; United States National Institutes of Health; Work; adipokines; clinical care; cohort; diabetes risk; euglycemia; evidence base; fasting glucose; high risk; immune activation; improved; low and middle-income countries; mouse model; multidisciplinary; novel marker; participant enrollment; prevent; prospective; stress management; theories; tissue biomarkers; treatment guidelines; treatment risk; tuberculosis treatment

PROJECT SUMMARY The intersection of tuberculosis (TB) with non-communicable diseases, including diabetes mellitus, has emerged as a critical clinical and public health obstacle. Rapidly expanding diabetes epidemics threaten TB control in low- and middle-income countries, including the country of Georgia, where preventing and treating TB disease remains a great burden. However, to date, the notion that TB disease may increase the risk of metabolic diseases like diabetes has not been well explored. This study will determine the extent to which TB-induced stress hyperglycemia impacts the risk of poor TB treatment outcomes. We will also assess whether stress hyperglycemia or adipose tissue inflammation during TB increase the risk of diabetes post-TB. This research will advance understanding of dual burdens of TB-diabetes and inform treatment guidelines for management of stress hyperglycemia during TB. The long-term objective of this research is to develop an evidence base to help identify which patients with TB are likely to benefit most from adjunctive anti-inflammatory glucose-lowering agents. The specific aims of this proposal are to: (1) determine the relationship between stress hyperglycemia and TB outcomes, including TB cure rate and time to sputum culture conversion; (2) determine the extent that stress hyperglycemia during TB increases the risk of diabetes 1-year after TB treatment; and (3) explore the relationship between plasma and subcutaneous tissue biomarkers of adipose tissue inflammation with stress hyperglycemia and diabetes risk. The aims of this project will be achieved by enrolling a cohort of patients at the time of TB diagnosis and following them prospectively during treatment and for 1-year post-TB treatment. At multiple time points during this study we will measure glucose, insulin resistance, lipids, adipokines, and anthropometry among participants with diabetes, stress hyperglycemia, and euglycemia. In a subset of the cohort we will perform adipose tissue biopsies and measure adipose tissue inflammation. The analyses will include multiple modeling strategies to assess the relationship between patient and host factors and the risk of post-TB metabolic disease. This proposal will directly address clinical uncertainties related to the growing global concern of intersecting TB and diabetes epidemics. The study will help to characterize the extent to which TB contributes to diabetes incidence and will identify which patients with hyperglycemia are at greatest risk of poor TB outcomes. In addition, this R01 will explore novel biomarkers of adipose tissue inflammation to determine whether TB alters immune activity or metabolic function within human adipose tissue. A long-term goal of the proposed work is to prepare for prospective interventional studies that will evaluate glucose-lowering agents during active TB as adjunctive therapy to improve TB outcomes and reduce risk of diabetes after TB.

项目概要 结核病 (TB) 与糖尿病等非传染性疾病的交叉现象已经出现 作为一个关键的临床和公共卫生障碍。迅速蔓延的糖尿病流行威胁着低收入国家的结核病控制 和中等收入国家，包括格鲁吉亚国家，结核病的预防和治疗仍然存在 一个很大的负担。然而，迄今为止，人们认为结核病可能会增加代谢性疾病的风险，例如 糖尿病尚未得到很好的探索。这项研究将确定结核病引起的应激性高血糖的程度 影响结核病治疗结果不佳的风险。我们还将评估压力性高血糖或脂肪是否 结核病期间的组织炎症会增加结核病后患糖尿病的风险。这项研究将增进对 结核病-糖尿病的双重负担，并为结核病期间应激性高血糖的管理提供治疗指南。 这项研究的长期目标是建立证据基础，帮助确定哪些结核病患者 可能从辅助抗炎降糖药中获益最多。本次活动的具体目标 建议是：(1) 确定应激性高血糖与结核病结局（包括结核病治愈）之间的关系 痰培养转化率和时间； (2)确定TB期间应激性高血糖增加的程度 结核病治疗后一年患糖尿病的风险； (3)探讨血浆与皮下组织之间的关系 脂肪组织炎症的组织生物标志物与应激性高血糖和糖尿病风险。本次活动的目的 该项目将通过在结核病诊断时招募一组患者并对他们进行前瞻性跟踪来实现 治疗期间和结核病治疗后 1 年。在本研究期间的多个时间点，我们将测量 糖尿病、压力参与者的血糖、胰岛素抵抗、血脂、脂肪因子和人体测量 高血糖和血糖正常。在队列的一个子集中，我们将进行脂肪组织活检并测量 脂肪组织炎症。分析将包括多种建模策略来评估关系 患者和宿主因素与结核病后代谢性疾病风险之间的关系。 该提案将直接解决与全球日益关注的交叉结核病相关的临床不确定性 和糖尿病流行。该研究将有助于确定结核病导致糖尿病的程度 发病率，并将确定哪些高血糖患者出现结核病结局不良的风险最大。此外， 该 R01 将探索脂肪组织炎症的新型生物标志物，以确定结核病是否会改变免疫 人体脂肪组织内的活动或代谢功能。拟议工作的长期目标是为 前瞻性干预研究将评估活动性结核病期间降糖药物作为辅助治疗的作用 改善结核病治疗结果并降低结核病后患糖尿病的风险。