John Corbett

My lab focuses on mechanisms that are responsible for the loss of function and damage to beta-cell during diabetes development using molecular, biochemical, transgenic, and immunological approaches. In particular, we seek to understand the mechanisms responsible for controlling beta-cell fate in response to cytokines, both the damaging aspects of this response as well as the protective pathways regulated by cytokines and nitric oxide. We identified nitric oxide as mediator of the inhibitory actions of IL-1 on insulin secretion and found that beta cells are the islet cellular source of this nitric oxide. We found that human islets are capable of expressing iNOS and producing high levels of nitric oxide in vitro, and that nitric oxide mediates the inhibitory actions of IL-1 and IFN-γ on insulin secretion by human islets. We have also provided evidence that IL-1, produced locally in islets by activated tissue macrophages, can cause beta-cell damage in a nitric oxide dependent manner (in rodent and human islets). Additionally, we have pioneered studies on the functional recovery of beta-cells from cytokine-mediated damage and have shown that this process requires new gene expression and is stimulated by nitric oxide. More recently, we have shown that the DNA damage response (DDR), and specifically the kinase ATM, is responsible for triggering beta-cell apoptosis in response to cytokine treatment and that nitric oxide is a direct regulator of the DDR in beta-cells.