A pathological feature of both type 1 and type 2 diabetes is loss of pancreatic beta cell mass through increased apoptosis. The molecular mechanisms mediating increased apoptosis are unknown but new evidence links the beta cell glucose sensor “glucokinase” to beta cell survival. The proapoptotic protein BAD is localised with glucokinase in beta cells potentially linking glucose homeostasis with beta cell functional integrity1. Exposure of islets to proinflammatory cytokines or glucolipotoxic conditions activate beta cell apoptotic pathways with concommitent decreases in beta cell insulin secretory function. Glucokinase has been implicated as a mediator of beta cell dysfunction in both cytokine and glucolipotoxic conditions2,3. Molecular compounds which bind to an allosteric activation site on glucokinase have recently been developed. GKA50 is a potent activator of glucokinase which increases enzyme activity with enhanced insulin secretion in vitro and in vivo. Given the probable role of glucokinase in the regulation of beta cell survival/apoptosis we have used GKA50 to elucidate the effects of increased glucokinase activation on glucolipotoxic and cytokine induced beta cell integrity and insulin secretion (using the rat-derived beta cell line BRIN-BD11). Apoptosis was induced by culturing cells in the presence of a lethal proinflammatory cytokine cocktail (IFNγ, IL-1β, TNFα) or chronic high glucose and lipid levels (25mM glucose ,100μM palmitate) for 24hr with or without GKA50. A thorough analysis of cell viability and apoptosis was performed. Cell apoptosis was examined by DNA fragmentation, LDH release and Trypan blue staining. Cell viability was determined by WST and neutral red assays and mitochondrial membrane potential. Chronic and acute stimulated insulin secretion was measured by ELISA. Significant cell death and impairment of insulin secretion occurred in pro-inflammatory or glucolipotoxic experimental conditions (p<0.05). When viability was examined after exposure to either cytokines or glucolipotoxic conditions those cells treated with GKA50 were protected from loss of membrane integrity as cells treated with GKA50 had a significantly reduced level of LDH release following incubation in glucolipotoxic conditions (p<0.05). However, DNA fragmentation which was enhanced by in pro-inlammatory cytokine or glucolipotoxic conditions, or suppressed levels of insulin secretion, were not altered by GKA50 addition. Glucokinase is a critical enzyme in beta cell physiology and its activity has important implications for metabolism and insulin secretion. However an increase in glucokinase activation does not alter DNA fragmentation responses or insulin secretion after incubation in either glucolipotoxic or pro-inflammatory cytokine conditions. However our results support the hypothesis that the detrimental effects of cytokines or glucolipotoxicity occurs via a post-glycolytic event.