Vascular pathology is recognized as a principle insult in type 2 diabetes mellitus (T2DM). Co-morbidities such as structural brain abnormalities, cognitive, learning and memory deficits are also prevailing in T2DM patients. We previously suggested that microvascular pathologies involving blood-brain barrier (BBB) breakdown results in leakage of serum-derived components into the brain parenchyma, leading to neuronal dysfunction manifested as psychiatric illnesses. The current postulate focuses on the molecular mechanisms controlling BBB permeability in T2DM, as key contributors to the pathogenesis of mental disorders in patients. Revealing the mechanisms underlying BBB dysfunction and inflammatory response in T2DM and their role in metabolic disturbances, abnormal neurovascular coupling and neuronal plasticity, would contribute to the understanding of the mechanisms underlying psychopathologies in diabetic patients. Establishing this link would offer new targets for future therapeutic interventions.