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

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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.