It is projected that by 2030, more than half a billion people will be suffering from type 2 diabetes (T2D) and majority of the increase will be due to patients living in the tropics. T2D contributes to chronic metabolic complications and increases the incidence and severity of infection. Patients with T2D are three times more susceptible to tuberculosis and ten times more sucessaptible to the tropical infection melioidosis. We have used samples from T2D patients and three different diabetic animal models to investigate the host-pathogen interactions that may contribute to this increased susceptibility using Burkholderia pseudomallei (Bps) as a model of severe infection. In human studies we have demonstrated that early interactions between Bps and phagocytes are altered in T2D with production of significantly higher levels of inflammatory cytokines (IL-12p70, MCP-1, and IL-8) compared to phagocytes from non-diabetics. Dendritic cells and macrophages from streptozotocin-induced diabetic mice with chronic hyperglycaemia showed impaired phagocytosis and killing of Bps. We demonstrated in a leptin receptor deficient (db/db) mouse model that defects in the early innate immune responses to Bps in these animals contributed to greater susceptibility. Furthermore we have characterised a high-fat diet (HFD)–fed mouse as a model for impaired glucose tolerance and T2D and have investigated inflammatory responses and survival following Bps infection. The initial systemic inflammatory cytokine response (TNF-α, MCP-1 and IL-12) was delayed in HFD-fed diabetic animals during the first 12 hrs of infection and by 24 hours post-infection Bps loads were significantly higher in spleen, liver and lung in diabetic compared to non-diabetic animals. Following an initial delay in cytokine production, an exaggerated proinflammatory cytokine response was observed in diabetic mice by 48hrs post-infection. Diabetic mice were highly susceptible to Bps infection, with a median survival of 4 days compared to 12 days for non-diabetic mice. Our data suggests that the dysregulated hyperinflammatory state in individuals with T2D and infection results in the high morbidity and mortality.