Therapeutic Restoration of Metabolic Homeostasis During Active TB

描述(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出现全身葡萄糖代谢的深刻变化，表现为血糖水平升高(高血糖)和糖耐量受损，只有在进行了几个月的抗菌药物治疗后，这种变化才能恢复正常。此外，结核病患者还会出现血清游离脂肪酸水平(FFAs)升高，在各种非结核病疾病中，FFAs已被证明是全身性胰岛素抵抗的有效中介。由于1)脂肪酸代谢改变与糖稳态失调直接相关，2)系统性胰岛素抵抗是糖耐量受损的最常见原因，我们将检验以下假设：结核分枝杆菌感染期间糖耐量受损是由于胰岛素抵抗，全身葡萄糖稳态的治疗恢复将减缓结核病的进展，并改善抗微生物药物治疗的反应。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，而且还将确定用降血糖药物恢复代谢平衡作为抗菌治疗的辅助是否有益。我们的初步数据显示，像人类一样，感染结核杆菌的豚鼠出现糖耐量受损和血清游离脂肪酸升高，高血糖会加剧结核病的严重程度。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下降，这被称为胰岛素抵抗。基于这些概念，我们将使用豚鼠结核病模型来确定糖耐量受损的分子机制，以及单独治疗或联合抗菌药物恢复葡萄糖稳态是否改善宿主对结核分枝杆菌感染的反应。在目标1中，我们将确定糖耐量受损和由此导致的高血糖是否是由脂质第二信使二酰甘油(DAG)的亚细胞分布和积累所介导的全身性胰岛素抵抗所致。在目标2中，我们将确定FDA批准的降糖药物是否能够恢复和维持全身血糖平衡，从而减缓结核杆菌感染的豚鼠的结核病进展。我们还将确定，当降糖药物与抗微生物药物联合使用时，是否会改善结核病的治疗反应。总的来说，这些研究将确定在结核杆菌感染期间观察到的改变的葡萄糖代谢是否有助于结核病的发病，以及代谢稳态的治疗性恢复是否会改善抗微生物药物的治疗反应。这些研究解决了对改进当前结核病药物治疗的创新战略的迫切需求，这些需求尚未得到满足。

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.