Therapeutic Restoration of Metabolic Homeostasis During Active TB

活动性结核病期间代谢稳态的治疗性恢复

• 批准号: 8773050
• 负责人: Randall J Basaraba
• 金额: $ 22.31万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773050
• 关键词: 1,2-diacylglycerol; Address; Adipose tissue; Animal Model; Antibiotic Therapy; Antibiotics; Antitubercular Agents; Bacterial Infections; Blood Glucose; Carrier Proteins; Cavia; Chronic; Clinical Research; Combination Drug Therapy; Communicable Diseases; Data; Diabetes Mellitus; Diglycerides; Disease; Disease Progression; Drug usage; Dyslipidemias; Effectiveness; Euglycemic Clamping; FDA approved; Glucose; Glucose Clamp; Glucose Transporter; Homeostasis; Human; Hyperglycemia; Immune response; Infection; Insulin; Insulin Receptor; Insulin Resistance; Laboratories; Lead; Length; Lesion; Link; Lipids; Liver; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Mycobacterium tuberculosis; Nonesterified Fatty Acids; Pancreatic Hormones; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Predisposition; Protein Kinase C; Receptor Signaling; Research; Risk; Second Messenger Systems; Serum; Severity of illness; Skeletal Muscle; Techniques; Testing; Therapeutic; Time; Tissues; Tuberculosis; antimicrobial; antimicrobial drug; base; blood glucose regulation; diabetic; fatty acid metabolism; glucose metabolism; impaired glucose tolerance; improved; in vivo; innovation; insulin sensitivity; lipid metabolism; non-diabetic; public health relevance; response; restoration; second messenger; therapy design; treatment response; tuberculosis drugs; tuberculosis treatment; wasting

DESCRIPTION (provided by applicant): It is estimated that more than a third of the world's human population (over 2 billion people) are infected with Mycobacterium tuberculosis (Mtb). One of the major hurdles to controlling the global spread of TB is the length of time required to effectively treat patients with active TB disease. It has been known for decades that humans infected with Mtb develop profound alterations in systemic glucose metabolism reflected by elevated blood glucose levels (hyperglycemia) and impaired glucose tolerance, which is restored to normal only after months of antimicrobial drug therapy. Moreover, TB patients also develop elevated serum free fatty acid levels (FFAs), which in a variety of non-TB diseases have been shown to be potent mediators of systemic insulin resistance. Since 1) altered fatty acid metabolism is directly linked to dysregulated glucose homeostasis and 2) systemic insulin resistance is the most common cause of impaired glucose tolerance, we will test the hypothesis that: Impaired glucose tolerance during Mtb infection is due to insulin resistance and that therapeutic restoration of systemic glucose homeostasis will slow TB disease progression and improve antimicrobial drug treatment responses. In these studies we will not only determine the molecular pathogenesis of altered glucose metabolism associated with active Mtb infection but also determine whether restoring metabolic homeostasis with antiglycemic drugs is beneficial as an adjunct to antimicrobial therapy. Our preliminary data show that, like humans, Mtb infected guinea pigs develop impaired glucose tolerance and elevated serum FFAs and that hyperglycemia exacerbates TB disease severity. In non-TB diseases like diabetes, it is well accepted that hyperglycemia is due to impaired glucose tolerance resulting from decreased sensitivity of certain tissues (skeletal muscle, liver and adipose tissue) to the activity of the pancreatic hormone insulin, which is referred to as insulin resistance. Based on these concepts we will use the guinea pig TB model to determine the molecular mechanisms of impaired glucose tolerance and whether restoring glucose homeostasis therapeutically alone or in combination with antimicrobial drugs, improves host responses to Mtb infection. In Aim 1, we will determine whether impaired glucose tolerance and the resulting hyperglycemia is due to systemic insulin resistance mediated by the subcellular distribution and accumulation of the lipid second messenger diacylglycerol (DAG). In Aim 2, we will determine whether restoring and maintaining systemic glucose homeostasis with FDA approved, antiglycemic drugs will slow TB disease progression in Mtb-infected guinea pigs. We will also determine whether the use of antiglycemic drugs, when combined with antimicrobial drugs, improves TB treatment responses. Collectively, these studies will determine whether the altered glucose metabolism observed during Mtb infection contributes to TB pathogenesis and if therapeutic restoration of metabolic homeostasis improves antimicrobial drug treatment responses. These studies address an urgent, unmet need for innovative strategies to improve current TB drug treatments.

描述（由申请人提供）：据估计，超过三分之一的世界人口（超过20亿人）感染结核分枝杆菌（Mtb）。控制结核病全球传播的主要障碍之一是有效治疗活动性结核病患者所需的时间长度。几十年来已知感染Mtb的人发生全身葡萄糖代谢的深刻改变，其反映为血糖水平升高（高血糖症）和葡萄糖耐量受损，其仅在数月的抗微生物药物治疗后恢复正常。此外，TB患者还出现升高的血清游离脂肪酸水平（FFA），其在多种非TB疾病中已被证明是全身性胰岛素抵抗的有效介质。由于1）脂肪酸代谢改变与葡萄糖稳态失调直接相关，2）全身性胰岛素抵抗是葡萄糖耐量受损的最常见原因，我们将检验以下假设：Mtb感染期间葡萄糖耐量受损是由于胰岛素抵抗，治疗性恢复全身葡萄糖稳态将减缓TB疾病进展并改善抗微生物药物治疗反应。在这些研究中，我们不仅将确定与活动性结核分枝杆菌感染相关的葡萄糖代谢改变的分子发病机制，而且还将确定使用降糖药物恢复代谢稳态作为抗菌治疗的辅助治疗是否有益。我们的初步数据显示，与人类一样，结核分枝杆菌感染的豚鼠出现葡萄糖耐量受损和血清游离脂肪酸升高，高血糖症加剧了结核病的严重程度。在非TB疾病如糖尿病中，普遍认为高血糖症是由于某些组织（骨骼肌、肝脏和脂肪组织）对胰腺激素胰岛素活性的敏感性降低导致的葡萄糖耐量受损，这被称为胰岛素抵抗。基于这些概念，我们将使用豚鼠TB模型来确定葡萄糖耐量受损的分子机制，以及单独治疗或与抗微生物药物组合治疗是否恢复葡萄糖稳态，改善宿主对Mtb感染的反应。在目的1中，我们将确定糖耐量受损和由此产生的高血糖症是否是由于脂质第二信使甘油二酯（DAG）的亚细胞分布和积累介导的全身性胰岛素抵抗。在目标2中，我们将确定FDA批准的恢复和维持全身葡萄糖稳态的降糖药物是否会减缓结核分枝杆菌感染豚鼠的结核病进展。我们还将确定降糖药物与抗微生物药物联合使用是否能改善结核病治疗反应。总的来说，这些研究将确定Mtb感染期间观察到的葡萄糖代谢改变是否有助于TB发病机制，以及代谢稳态的治疗恢复是否改善了抗微生物药物治疗反应。这些研究解决了对创新策略的迫切需求，以改善当前的结核病药物治疗。