Cellular and spatial mechanisms underlying how inflammatory cytokines impact postprandial glucose responses in health and disease

炎症细胞因子如何影响健康和疾病中餐后葡萄糖反应的细胞和空间机制

基本信息

批准号：
10064841
负责人：
Gwendalyn J Randolph
金额：
$ 78.75万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2022-09-10
项目状态：
已结题

项目摘要

ABSTRACT The concept that inflammatory cytokine signaling underlies insulin resistance and thus contributes to pancreatic beta cell failure and type II diabetes is widely accepted. It is less clear, however, if cytokine-targeted therapeutics might improve glycemic excursions and insulin responses in humans, even though cytokine neutralizing therapies are widely used to treat other diseases, including many diseases that heighten risk for type II diabetes. The present catalyst proposal is prompted by an observation in our ongoing work in human subjects that unexpectedly suggests a novel cytokine(s) target that may hold promise for normalizing glucose metabolism in humans with inflammatory and metabolic disease. We will carry out further studies in human subjects already taking therapeutics targeting the neutralization of this cytokine(s) to confirm and delineate its effects and to consider mechanism of action. This research will be linked to work in mouse models, as hints in the literature related to the cytokine(s) suggest that work in mouse will hold at least partial parallels with the human and can be used to delineate details in the mechanism of action, including the cell sources of the cytokine(s) and the spatial tissue environment in which the cytokine acts to undermine glucose metabolism. The work may lead to a repurposing of existing therapeutics to treat diseases linked to poor glucose metabolism.

抽象的炎症细胞因子信号传导是胰岛素抵抗的基础，因此有助于胰腺β细胞衰竭和II型糖尿病已被广泛接受。然而，目前尚不清楚，细胞因子是否靶向治疗方法可能会改善人类的血糖波动和胰岛素反应，尽管细胞因子中和疗法广泛用于治疗其他疾病，包括许多增加风险的疾病 II型糖尿病。目前的催化剂提议是由我们正在进行的人类工作中的观察引发的受试者出乎意料地提出了一种新的细胞因子靶点，该靶点可能有望使血糖正常化患有炎症和代谢疾病的人类的新陈代谢。我们将在人类方面进行进一步的研究已接受针对中和该细胞因子的治疗的受试者，以确认和描述其效果并考虑作用机制。这项研究将与小鼠模型的工作联系起来，正如与细胞因子相关的文献表明，在小鼠中的工作至少部分与人类，可用于描绘作用机制的细节，包括细胞来源细胞因子和细胞因子发挥作用破坏葡萄糖代谢的空间组织环境。这项工作可能会导致现有疗法的重新利用，以治疗与血糖不足相关的疾病代谢。