Metabolic inflammation in type-2 diabetes (T2D) is initiated by type-1 interferon signalling, through its transcriptional mediator IRF5. Whilst studies in auto-immunity link pro-inflammatory polarisation to increased glycolysis, this phenomenon remains unexplored in T2D or in the context of IRF5-dependent inflammation. We hypothesise that macrophage bioenergetic adaptation in T2D is distinct, due to the distinct nature of insult and systemic abundance of substrates. IRF5 may play a key role in adapting cellular bioenergetics to initiate, amplify and sustain inflammation. To address these hypotheses, we analysed public and in-house sequencing datasets and carried out mechanistic in vivo and ex vivo analyses.