NAMPT activity plays a key role in driving autoimmune processes that mediate beta-cell death and type 1 diabetes development in mice

Type 1 diabetes (T1D) is characterised by destruction of pancreatic beta-cells by islet-infiltrating cytotoxic lymphocytes and elevated intra-islet secretion of pro-inflammatory cytokines. However, the underlying pathophysiological mechanisms remain incompletely understood. We hypothesised that abnormal elevation of islet NAD, via activation of NAMPT, plays a key role in driving islet autoimmune processes, leading to beta-cell death in T1D. Here, we report that NAMPT inhibition protects against pro-inflammatory cytokine (IL-1β, TNFα and IFNγ) mediated beta-cell dysfunction and apoptosis in isolated mouse and human islets. RNAseq revealed that NAMPT inhibition blocked cytokine-mediated gene expression linked to pro-inflammatory responses and leukocyte migration. In vivo, diabetes was induced in CD1 mice via multiple low-dose streptozotocin (MLDS) injections. MLDS mice were administered the NAMPT inhibitor FK866 (10 mg/kg; IP) or saline equivalent for 16 days. These experiments demonstrated that NAMPT inhibition improved glycaemic control and beta-cell survival and function in MLDS mice. FK866 also reduced proportions of islet-residing TNFα-producing CD4+T-cells and F4/80+macrophages, proliferation of spleen-derived CD4+ and CD8+T-cells and proliferation of islet-derived CD4+T-cells and F4/80+macrophages. Finally, we report that NAMPT inhibition was able to block pro-inflammatory cytokine-mediated migration of cytotoxic CD8+T-cells into isolated islets, using an in vitro transwell platform. This data supports a key immunomodulatory role for NAMPT in islet autoimmunity. NAMPT inhibition may be able to prevent beta-cell death and thus represent a novel therapeutic approach for T1D. The effects of increased NAD levels on islet inflammation require in-depth characterisation and caution should be exercised with regard to the use of NAD boosting supplements, particularly in individuals at risk of developing T1D.