Tobacco smoke (TS) is accountable for ≈ 434,000 casualties/year in the US and is the leading cause of preventable death. Even though there has been a marginal decline in smoking during recent years, the fact that ≈ 18% of the US adult population are current smokers is alarming [1]. In 2007 diabetes was the 7th leading cause of death in the US and increasing at an alarming rate. One in every three U.S. adults is projected to suffer from diabetes by 2050 [2]. Smoking is a major risk factor for diabetes [3], with 12% of Type-2 Diabetes Mellitus (T2DM) cases being attributed to tobacco smoke (45% higher in men, 74% higher in women in comparison to non-smokers) [4-6]. Both active and passive smoking not only causes glucose intolerance [7], but also significantly increases the risk of diabetes. Major pathological changes in diabetic patients such as insulin resistance and high levels of glycated hemoglobin (HbA1c) have also been reported in smokers [5]. Similarly to TS, the risk of myocardial infarction and stroke is 4-fold higher in 2DM independently of other known risk factors [8]. Both T2DM and TS have independently been reported to enhance the risk of cerebrovascular and neurological disorders, however the pathophysiological mechanisms underlying these cerebrovascular disorders remain elusive. CS contains over 4000 chemicals including nicotine and various reactive oxygen species (ROS) (e.g., H2O2, epoxides, nitrogen dioxide, peroxynitrite -ONOO-, etc. [9,10] which pass through the lung alveolar wall and raise systemic oxidative stress OS [11]. At the cerebrovascular level this promotes oxidative damage and BBB breakdown via tight junction (TJ) modification and activation of pro inflammatory pathways [12,13]. Under normal conditions, ROS are scavenged by antioxidant vitamins such as ascorbic acid and α-tocopherol [14-17] or intracellularly converted into less reactive molecules by superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) [18]. Both acute and chronic nicotine exposure has even shown to reduce stroke induced enhancement in GLUT1 transport function and expression at the BBB in a focal brain ischemia model [19]. However, chronic exposure to active and passive smoking can overwhelm these protective mechanisms. Elevated levels of WBC, primarily neutrophils and monocytes, are observed in smokers [20]. In particular, neutrophils, which secrete free radicals, elastase and collagenase [21], are thought to contribute directly to endothelial cells (EC) injury. Platelet activation is also frequently observed in smokers [22] and confirmed in vitro and in vivo studies [23].