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

摘要 炎症细胞因子信号传导是胰岛素抵抗的基础，因此有助于胰岛素抵抗的概念， 胰腺β细胞衰竭和II型糖尿病被广泛接受。然而，不太清楚的是， 治疗可能改善人类的血糖波动和胰岛素反应，即使细胞因子 中和疗法被广泛用于治疗其他疾病，包括许多增加感染风险的疾病。 II型糖尿病目前的催化剂建议是由我们正在进行的人类研究工作中的观察引起的。 受试者意外地提出了一种新的细胞因子靶点，可能有望使葡萄糖正常化 在患有炎症和代谢性疾病的人中的代谢。我们将在人类中进行进一步的研究。 已经服用靶向中和该细胞因子的治疗剂的受试者，以确认和描述其 影响，并考虑作用机制。这项研究将与小鼠模型的工作联系起来， 与细胞因子相关的文献表明，在小鼠中的工作将至少部分地与 人，并可用于描述作用机制的细节，包括细胞来源， 细胞因子和空间组织环境，其中细胞因子起破坏葡萄糖代谢的作用。 这项工作可能会导致现有疗法的重新利用，以治疗与葡萄糖不足有关的疾病 新陈代谢.

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.