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. 1. Introduction: The Vascular Hypothesis Macro- and microvascular complications involving endothelial dysfunction are central to the pathogenesis and clinical manifestations of type 2 diabetes mellitus (T2DM) [1]. Structural brain abnormalities [2–7] and cognitive, learning and memory deficits were demonstrated in T2DM patients [8–10]. We recently published a hypothesis paper suggesting that a primary vascular pathology involving inflammatory cascade and Blood-Brain Barrier (BBB) breakdown, will result in the leakage of serum-derived vascular components into the brain tissue and may cause brain dysfunction which, under some conditions (extent, duration, and/or location), will result in disturbed thinking processes, mood, and behavior, such as those characterizing psychiatric illnesses [11]. The current postulate focuses on inflammation and molecular mechanisms controlling BBB permeability in T2DM as key contributors to the pathogenesis of mental disorders in diabetic patients and suggests novel targets for the prevention and treatment of cognitive and psychiatric complications. 2. Type 2 Diabetes Mellitus and Vascular Pathology T2DM is a multifactorial metabolic disorder. The underlying etiology, pathophysiology and complications of diabetes are still being elucidated (for review see [12]). T2DM is characterized by chronic abnormal high blood glucose levels (hyperglycemia), insulin resistance, and a relative insulin secretion defect [13]. Induction of insulin resistance is linked to obesity and activation of neuroendocrine and inflammatory responses [14–16].
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