| Project Detail |
Though it has long been known that activated lymphoid cells upregulate insulin receptors, the functional relevance of insulin signalling in immune cells has only recently begun to be explored. This includes the recent finding that insulin-stimulated activation in the PI3K/Akt/mTOR promotes immunometabolic reprogramming of T cells, thereby promoting antigen-specific immunity. Similarly, in liver cells, insulin receptors have been shown to translocate to the nucleus where they participate in regulating genes involved in viral response and epitope presentation. Whats more, various lines of evidence have implicated inulin signalling in the development of coagulopathies, via its effect on the expression of cytokines, complement and clotting factors, whiles also affecting platelets and endothelium. Taken together, these and other observations implicate an under-appreciated immune-regulatory function of insulin. Yet, even basic questions regarding insulin signalling in immune cells (e.g. do T cells develop insulin resistance?) are currently unknown. In the proposed study, we will investigate the effect of insulin signalling in immune and non-immune cells to evaluate the impact of insulin signalling on these immune-related functions. Firstly, we will leverage publicly available proteome and transcriptome data to re-interrogate these data sets from an immunological perspective. Complimenting these activities, we will also conduct detailed cell culture experiments to evaluate the effect of (a) does and (b) duration of insulin on the release of clotting factors, cytokines and complement, as well as immune cell activation and polarization. Finally, we will conduct a vaccine trial on a rodent model to evaluate the effect of insulin on vaccine efficacy. Beyond T1D and T2D, these findings will also impact diabetic care in organ transplant, gestational diabetes and the development of pre-eclampsia, immunotherapies, and intensive insulin therapy in critical/intensive care. |
