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

项目摘要 结核病与包括糖尿病在内的非传染性疾病的交叉已经出现 严重的临床和公共卫生障碍。糖尿病流行的迅速扩大威胁着低- 在包括格鲁吉亚在内的中等收入国家，预防和治疗结核病仍然是一项艰巨的任务， 一个巨大的负担然而，迄今为止，结核病可能增加代谢性疾病风险的观点， 糖尿病尚未得到很好的研究。这项研究将确定结核病引起的应激性高血糖的程度 影响结核病治疗效果不佳的风险。我们还将评估是否有应激性高血糖或脂肪 结核病期间的组织炎症会增加结核病后患糖尿病的风险。这项研究将促进对 结核病-糖尿病的双重负担，并为结核病期间的应激性高血糖管理提供治疗指南。 这项研究的长期目标是建立一个证据基础，以帮助确定哪些结核病患者 可能从连续性抗炎降糖药中获益最多。具体目标是 建议：（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 痰培养转换率和时间;（2）确定TB期间应激性高血糖增加的程度 结核病治疗后1年患糖尿病的风险;（3）探讨血浆和皮下组织中结核病的关系。 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。其目的是 该项目将通过在结核病诊断时招募一组患者并前瞻性随访来实现 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、糖尿病患者的血糖、胰岛素抵抗、血脂、脂肪因子和人体测量 高血糖症和血糖正常。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，以评估关系 患者和宿主因素与结核病后代谢疾病风险之间的关系。 该提案将直接解决与交叉结核日益增长的全球关注相关的临床不确定性 和糖尿病流行。这项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是结核病预后不良的最大风险。此外，本发明还提供了一种方法， 该R 01将探索脂肪组织炎症的新生物标志物，以确定结核病是否改变免疫功能， 人体脂肪组织内的活性或代谢功能。拟议工作的长期目标是为 前瞻性干预性研究，将评价活动性TB期间的降糖药物作为连续治疗 改善结核病的预后并降低结核病后患糖尿病的风险。

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.