The Role of Lymphocytes in Diet-Induced Metabolic Disease

描述（由申请人提供）：胰岛素抵抗（IR）和2型糖尿病（T2 D）作为慢性炎症性疾病的认识使得免疫代谢新领域的开发成为必要，这将定义免疫系统在代谢疾病中的作用。最近的动物研究表明，炎性T细胞和B细胞在2型糖尿病IR的发展中起关键作用。例如，在扩大的饮食诱导的肥胖（DIO）小鼠脂肪组织（AT）中，T细胞向促炎性Th 17和Th 1亚群倾斜以及Th 17/Th 1数量升高促进炎症，从而促进IR（1，5）。重要的是，Th 17和Th 1细胞分别是IL-17和IFN-γ的主要来源，IL-17和IFN-γ是两种促炎、抗脂肪形成、IR相关的细胞因子。补充研究表明，抗炎调节性T细胞（Tcells）的损失增加了AT炎症和血清胰岛素水平，而Treg功能的获得减少了AT炎症并挽救了葡萄糖敏感性。总之，这些研究表明，促炎性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。像这些小鼠研究一样，我们开创性的人体免疫代谢工作确定了T2 D患者血液中的促炎性T细胞亚群平衡：促炎性Th 17和Th 1细胞升高，抗炎性T细胞减少。此外，我们发现来自T2 D患者的血液B细胞是促炎性的。重要的是，新的数据显示T细胞/B细胞相互作用对于T2 D中Th 17功能升高至关重要; 因此，我们已经在人类样本中启动了一些第一个机制免疫代谢研究。总之，我们的工作表明，详细的人类免疫细胞分析将确定IR/T2 D的新机制，从而在评估和治疗策略中引入新概念。此外，对IR/T2 D个体中的人类免疫系统的详细分析对于证明利用免疫系统作为T2 D的生物标志物和/或治疗的尝试是绝对必要的。我们推测，我们在T2 D 1中发现的促炎性T细胞功能升高。来自单个个体的血液和AT相似; 2.预测肥胖患者的IR和/或AT功能;和3.需要B细胞的支持，可以用FDA批准的药物安全地消融。测试这些假设将评估创新的可能性，一个简单的血液测试（T细胞亚群分析）可以识别从胰岛素敏感性转变为IR的风险。这种测试的可用性将是一个重大的进步，具有直接的临床影响。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.