Severe Mental Illness (SMI) is often associated with metabolic alteration and/or metabolic syndrome, which may determine an increased mortality due to a further increased cardiovascular risk. The relationship with metabolic syndrome is often bidirectional, resulting in a pathoplastic effect of these dysmetabolisms. Among the several hormones involved, insulin appears to play a key role, albeit not entirely clear. The aim of our real-world cross-sectional observational study is to investigate a set of metabolic biomarkers of illness relapse/recurrence/onset in a cohort of 310 adult SMI inpatients consecutively admitted to the Psychiatry Clinic of the Azienda Ospedaliero Universitaria of Marche, in Ancona (Italy), between February 2021 and February 2024. According to the stepwise multivariate regression model, a higher number of acute episodes per year was positively predicted by the age of illness onset, the lifetime number of suicidal attempts and fasting insulinemia and negatively by the participant's age. A second stepwise multivariate regression model using only the metabolic characteristics as independent variables, found that a higher number of acute episodes per year was predicted positively by the fasting insulinemia and red blood cells and negatively by the abdominal circumference. Overall, our findings could provide practical implications for the treatment and management of SMI patients, emphasizing the importance of monitoring and managing metabolic factors, particularly insulinemia, metabolic syndrome and insulin resistance. Finally, insulinemia could potentially act as metabolic biomarker of illness relapse, though more larger and longitudinal studies should be carried out to confirm these results.