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A20 is a negative regulator of nuclear factor (NF)-κB-dependent inflammatory reaction in response to different stimuli by immune cells including dendritic cells (DCs), the most potent antigen-presenting cells involved in both the innate and adaptive immune response. Dendritic cells use glucose as carbon source to synthesize fatty acid and generate energy. Glucose enhances cell apoptosis mediated through PI3K/Akt, ERK1/2, and Bax/Bcl-2 pathways. The protein kinase Akt2/PKBβ is expressed in DCs and a regulator of Ca2 + influx, Na + /H + exchanger activity, and migration of DCs. This study explored whether regulation of high glucose-induced DC function through Akt2 signaling is influenced by overexpression of A20. To this end, A20 protein expression was determined by western blotting and immunoprecipitation, secretion of inflammatory cytokines by ELISA, and expression of apoptotic markers by flow cytometry. As a result, treatment of mice with 10% high glucose enriched water increased secretion of insulin/IGF1 and reduced A20 protein level, the effects were blunted in Akt2 -/- mice. Incubation of DCs with high glucose significantly decreased A20 protein expression in both control and Akt1 -silenced DCs, but not in Akt2 -/- DCs. Importantly, treatment of DCs with high glucose increased ceramide synthesis, caspase 8 activity, and annexin V binding in control DCs, the effects were abolished in Akt2 -/- DCs or by A20 overexpression. In conclusion, regulation of A20 sensitive DC function by high glucose is mediated through insulin/IGF-1/Akt2 signaling.