Therapeutic Restoration of Metabolic Homeostasis During Active TB

描述（由申请人提供）：据估计，世界上超过三分之一的人口（超过20亿人）感染了结核分枝杆菌（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，人们已经知道，感染结核分枝杆菌的人会发生全身糖代谢的深刻改变，这反映在血糖水平升高（高血糖）和葡萄糖耐量受损上，只有在几个月的抗菌药物治疗后才能恢复正常。此外，结核病患者还会出现血清游离脂肪酸水平（FFAs）升高，这在多种非结核病疾病中已被证明是全身性胰岛素抵抗的有效介质。由于1)脂肪酸代谢的改变与葡萄糖稳态失调直接相关，2)全身胰岛素抵抗是糖耐量受损的最常见原因，我们将验证以下假设：结核杆菌感染期间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结核病的进展并改善抗菌药物治疗反应。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糖代谢改变的分子发病机制，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是否有益。我们的初步数据显示，与人类一样，感染结核分枝杆菌的豚鼠出现糖耐量受损和血清游离脂肪酸升高，高血糖加剧了结核病的严重程度。在糖尿病等非结核病疾病中，人们普遍认为高血糖是由于某些组织（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而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，我们将使用豚鼠结核模型来确定糖耐量受损的分子机制，以及单独治疗或与抗菌药物联合恢复葡萄糖稳态是否能改善宿主对结核分枝杆菌感染的反应。在Aim 1中，我们将确定糖耐量受损和由此产生的高血糖是否是由于脂质第二信使二酰基甘油（DAG）的亚细胞分布和积累介导的全身性胰岛素抵抗。在Aim 2中，我们将确定使用FDA批准的降糖药物恢复和维持全身葡萄糖稳态是否会减缓mtb感染豚鼠的结核病进展。我们还将确定降糖药与抗菌药物联合使用是否能改善结核病治疗反应。总的来说，这些研究将确定结核分枝杆菌感染期间观察到的葡萄糖代谢改变是否有助于结核病的发病机制，以及代谢稳态的治疗性恢复是否能改善抗菌药物治疗反应。这些研究解决了一项迫切的、尚未得到满足的需求，即采用创新战略来改进目前的结核病药物治疗。

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.