Intracellular nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway. Abnormally elevated NAMPT can promote autoimmune and inflammatory processes. Many of these processes are key to type 1 diabetes (T1D) pathogenesis. Whilst NAMPT has been examined in other inflammatory diseases, the role of NAMPT in T1D remains unclear. To investigate the role of NAMPT in T1D, we used small molecule NAMPT modulators to determine the role of abnormally elevated NAMPT levels and activity in cytokine-mediated beta-cell death and dysfunction in mouse and human islets. Islets were isolated from Cd1 mice and incubated for 24 h with either NAMPT inhibitor (1020 nM FK866 or 200400 nM C17) or activator (510 μM P7C3) +/− proinflammatory cytokine cocktail (1 ng/ml). Islet function and survival were assessed via static glucose-stimulated insulin secretion (GSIS) assays, Caspase 3/7-glo bio-luminescence assay, and qPCR analysis. NAMPT inhibition protected islets against cytokine-induced apoptosis; cytokine-mediated caspase 3/7 activity was significantly reduced by ˜55% (P<0.01; C17) and ˜48% (P<0.001; FK866), compared with cytokine treatment alone. Co-incubation with 5 μM P7C3 exerted no significant changes in apoptosis compared to cytokine treatment alone (n=3). The pro-survival effects of NAMPT inhibition were not due to changes at gene expression level in either IL-1B or TNFA, nor in markers of intrinsic apoptosis (BAX, BAD & NOXA) since mRNA levels of these genes were unchanged between islets co-incubated with C17 and cytokines and islets incubated with cytokines alone (n=3). In addition, NAMPT inhibition with C17 or FK866 protected islets against pro-inflammatory cytokine-mediated reductions in GSIS (both P<0.0001). Surprisingly, P7C3 also exerted mild protective effects against cytokine-mediated reductions in GSIS (NS; n=2). NAMPT inhibition reversed cytokine-mediated beta-cell apoptosis and dysfunction. This suggests that NAMPT may play a pathophysiological role in mediating inflammation-induced beta-cell damage and thus, may be a therapeutic target.