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

摘要 炎性细胞因子信号是胰岛素抵抗的基础，因此有助于 胰岛β细胞衰竭和II型糖尿病被广泛接受。然而，不太清楚的是，是否有细胞因子靶向 治疗可能会改善人类的血糖漂移和胰岛素反应，即使细胞因子 中和疗法被广泛用于治疗其他疾病，包括许多增加罹患 II型糖尿病。本催化剂建议是由我们在人类正在进行的工作中观察到的 意外提出一种新的细胞因子(S)靶点的受试者，该靶点可能有望使血糖正常化 炎症性和代谢性疾病患者的新陈代谢。我们将对人类进行进一步的研究 已经在服用中和这种细胞因子的治疗药物的受试者(S)证实并描绘了它 并考虑其作用机制。这项研究将与在小鼠模型中的工作相联系，如 与细胞因子相关的文献(S)表明，在小鼠身上的工作将至少有部分与 可以用来描述作用机制中的细节，包括 细胞因子(S)和细胞因子破坏葡萄糖代谢的空间组织环境。 这项工作可能导致现有疗法的重新用途，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.