Insulin dysregulation (ID) in the horse is receiving increasing attention as a serious health concern, in particular due to its association with the potentially career or life ending condition, laminitis. The role of inflammation and the immune system in ID as well as its associated health concerns has also been raised. However, the involvement of inflammation in and mechanisms behind ID in the horse remain unclear. Therefore, our overall hypothesis was that due in part to changes in their gut microbiota and plasma lipidome, horses with ID have changes in circulating proinflammatory markers, in particular in response to glycemic challenge, that further drive metabolic dysfunction. This work focuses on 7 potential associations between ID and inflammation to test this hypothesis; (H1) horses with ID will have an abnormal inflammatory response to glycemic challenge, (H2) ID horses will have differences in their gut microbiota compared to metabolically normal controls, (H3) these horses will likewise have differences in their plasma lipidome, (H4) response to routine vaccination will be reduced in horses with ID compared to metabolically normal controls, (H5) circulating endotoxin concentrations will be elevated in horses with ID, in particular in response to glycemic challenge, and their inflammatory and metabolic responses will be improved following supplementation with a gut modulating mannan rich fraction of the yeast cell wall, (H6) whole blood stimulation with endotoxin will induce TLR4 mediated inflammatory gene expression, and (H7) changing circulating lipid concentrations will improve both glycemic and inflammatory parameters in ID horses. Overall this work provides insight into contributing factors to ID in the horse, in particularly as they relate to inflammation.