Inflammation in human obesity and type 2 diabetes

 描述（由申请方提供）：炎症通常是肥胖动物发生胰岛素抵抗所必需的，这与炎症使肥胖人群代谢不健康的证据一致。相比之下，炎症可以忽略不计的肥胖人群通常代谢健康。炎症作为肥胖相关代谢下降的加速剂的作用表明，炎症特征可以预测从肥胖/代谢健康到肥胖/胰岛素抵抗/2型糖尿病（T2 D）的转变。我们提出的工作将全面定义T2 D病因和发病机制期间的炎症特征，以填补1.识别最有可能因肥胖而转变为T2 D的人; 2.因此，针对新靶点的治疗提高了目前抗炎药物在T2 D中的适度疗效;和3.使用靶向治疗将肥胖与炎症介导的并发症（如T2 D和心血管疾病）分开。我们已经使用多变量数学方法来识别先前未被认识到的炎症特征，其区分肥胖/非T2 D、肥胖/前T2 D和肥胖/T2 D受试者。该特征包括多种T细胞细胞因子，其中许多优先由Th 17或Th 1 T细胞亚群产生。我们对人类T细胞炎症特征的鉴定，加上对“致糖尿病”炎症的其他推定来源的分析的拟议扩展，为解决炎症与T2 D发病机制之间关系中的重要突出问题提供了独特的机会。我们将通过一个纵向多PI项目检验一个假设，即区分T2 D与非T2 D受试者的T细胞特征是T2 D发病机制的预测性生物标志物，该项目涉及人类免疫代谢、细胞因子网络建模和肥胖临床研究方面的专家。通过拟议的工作验证的细胞因子签名将识别需要更密集的监测，干预或新的抗炎药物来延迟或预防肥胖相关的T2 D的人的可能性具有改变临床实践的巨大潜力，强调了该项目的影响和紧迫性。

 DESCRIPTION (provided by applicant): Inflammation is generally required for the development of insulin resistance in obese animals, consistent with demonstrations that inflammation predisposes obese people to be metabolically unhealthy. In contrast, obese people with negligible inflammation are often metabolically healthy. The role of inflammation as an accelerator of obesity-associated metabolic decline indicates that an inflammatory signature can predict the transition from obese/metabolically healthy to obese/insulin resistant/type 2 diabetes (T2D). Our proposed work will comprehensively define inflammatory signature(s) during T2D etiology and pathogenesis to fill critical gaps in 1. Identifying people most likely to transition to T2D in response to obesity; 2. Pinpointing treatments to new targets thus improve the currently modest efficacy of anti-inflammatory drugs in T2D; and 3. Using targeted therapies to uncouple obesity from inflammatory-mediated complications such as T2D and cardiovascular disease. We have used a multivariate mathematical approach to identify a previously unappreciated inflammatory signature that differentiates obese/non-T2D, obese/pre-T2D and obese/T2D subjects. This signature includes multiple T cell cytokines, many of which are preferentially produced by the Th17 or Th1 T cell subsets. Our identification of a human T cell inflammatory signature coupled with the proposed extention of the analyses to additional putative sources of "diabetogenic" inflammation provide unique opportunities to address important outstanding questions in the relationship between inflammation and T2D pathogenesis. We will test the hypothesis that a T cell signature that distinguishes T2D from non-T2D subjects is a predictive biomarker for T2D pathogenesis through a longitudinal multiple-PI project involving experts in human immunometabolism, cytokine network modeling and clinical research in obesity. The possibility that a cytokine signature validated by the proposed work will identify people who require more intensive monitoring, intervention or new anti-inflammatory drugs to delay or prevent obesity-associated T2D has tremendous potential to change clinical practice, emphasizing both the impact and the urgency of the project.