The Role of Lymphocytes in Diet-Induced Metabolic Disease

描述(申请人提供)：胰岛素抵抗(IR)和2型糖尿病(T2D)被认为是慢性炎症性疾病，这需要开发新的免疫代谢领域，这将定义免疫系统在代谢性疾病中的作用。最近的动物研究表明，炎性T细胞和B细胞在T2D中IR的发生发展中起关键作用。例如，在不断扩大的饮食诱导肥胖(DIO)小鼠脂肪组织(AT)中，T细胞向促炎的Th17和Th1亚群倾斜，并增加Th17/Th1数量，从而促进炎症，因此IR(1，5)。重要的是，Th17和Th1细胞分别是IL-17和干扰素的主要来源，这两种细胞因子是促炎、抗脂肪和IR相关的细胞因子。补充研究表明，失去抗炎调节性T细胞(Tregs)会增加AT炎症和血清胰岛素水平，而Treg功能的增加会降低AT炎症并挽救血糖敏感性。综上所述，这些研究表明促炎T细胞平衡在IR中起着重要作用。类似的方法也表明B细胞促进炎症和IR。与这些小鼠研究一样，我们开创性的人类免疫代谢工作在T2D患者的血液中发现了促炎T细胞亚群平衡：促炎Th17和Th1细胞升高，抗炎Tregs减少。此外，我们发现T2D患者的血B细胞是促炎的。重要的是，新的数据显示T细胞/B细胞的相互作用是T2D患者Th17功能升高的关键； 因此，我们已经在人类样本中启动了一些机械性免疫代谢研究。综上所述，我们的工作表明，详细的人体免疫细胞分析将发现IR/T2D的新机制，从而为评估和治疗策略引入新的概念。此外，对IR/T2D患者的人类免疫系统的详细分析对于证明试图利用免疫系统的力量作为T2D的生物标记物和/或治疗是绝对必要的。我们假设，我们在T2D中发现的升高的促炎T细胞功能1.在血液和单个个体的AT中相似；2.预测肥胖患者的IR和/或AT功能；3.需要B细胞的支持，可以用FDA批准的药物安全地消融。检验这些假设将评估一种创新的可能性，即简单的血液测试(T细胞亚群分析)可以识别从胰岛素敏感型转变为胰岛素抵抗的风险。这种测试的可获得性将是一项重大进步，并将立即产生临床影响。除了初步确定IS/IR转换的生物标志物外，结果还将解决现有B细胞耗竭药物可能阻止IS/IR转换的新可能性。

DESCRIPTION (provided by applicant): The appreciation of insulin resistance (IR) and type 2 diabetes (T2D) as chronic inflammatory diseases has necessitated development of the new field of immunometabolism, which will define the role of the immune system in metabolic disease. Recent animal studies have shown that inflammatory T cells and B cells play key roles in the development of IR in T2D. For example, T cell skewing towards the pro-inflammatory Th17 and Th1 subsets and elevated Th17/Th1 numbers in the expanding diet-induced obesity (DIO) mouse adipose tissue (AT) promotes inflammation, thus IR (1, 5). Importantly, Th17 and Th1 cells are major sources of IL-17 and IFN-¿, respectively, two pro-inflammatory, anti-adipogenic, IR-linked cytokines. Complementary studies showed loss of anti-inflammatory regulatory T cells (Tregs) increases AT inflammation and serum insulin levels, while gain of Treg function decreases AT inflammation and rescues glucose sensitivity. Together, these studies show a pro-inflammatory T cell balance plays important roles in IR. Similar approaches also show B cells promote inflammation and IR. Like these murine studies, our pioneering human immunometabolism work identified a pro-inflammatory T cell subset balance in blood from T2D patients: pro-inflammatory Th17 and Th1 cells are elevated, and anti-inflammatory Tregs are reduced. Furthermore, we found that blood B cells from T2D patients are pro-inflammatory. Importantly, new data show T cell/B cell interaction is critical for elevated Th17 function in T2D; thus we have initiated some of the first mechanistic immunometabolism studies in human samples. Taken together, our work indicates that detailed human immune cell analysis will identify new mechanisms of IR/T2D thus introduce new concepts in assessment and treatment strategies. Furthermore, detailed analysis of the human immune system in IR/T2D individuals is absolutely essential to justify attempts to harness the power of the immune system as a biomarker and/or treatment for T2D. We hypothesize that the elevated pro-inflammatory T cell function we have found in T2D 1. is similar in blood and AT from a single individual; 2. Predicts IR and/or AT function in obesity patients; and 3. Requires support from B cells, which can be safely ablated with FDA-approved drugs. Testing these hypotheses would assess the innovative possibility that a simple blood test (T cell subset analysis) can identify risk of transition from insulin-sensitive to IR. The availability of such a test would be a major advance with immediate clinical impact. In addition to preliminarily identifying a biomarker for the IS/IR transition, outcomes will address the novel possibility that existing B cell depletion drugs may prevent the IS/IR transition.