Insulin resistance and hyperinsulinemia are critical to the development of type 2 diabetes mellitus. The pathogenesis, however, of the multiple complications and conditions associated with this disease such as increased risk for and decreased recovery from stroke is not yet understood. Chronic inflammation is a prominent component of diabetes and inflammatory processes mediated by cytokines are critical to the pathogenesis of stroke. Studies from our laboratory have shown that hyperinsulinemia-induced serine phosphorylation of insulin receptor substrate (IRS) proteins blocks the ability of IRSs to serve as a Janus kinase substrates, which leads to impaired cytokine signaling. In that, anti inflammatory molecules such as insulin-like growth factor (IGF)-1 and the cytokines interleukin (IL)-4 and -10, have been shown to signal through IRS proteins, we hypothesize that the balance between pro- and anti-inflammation is likely perturbed in the developing and frankly diabetic subject. In order to demonstrate that diabetes exacerbates pro-inflammatory processes in the CMS, causing increased morbidity and mortality of stroke, we will determine if type 2-like db/db mice have an enhanced IL-1-beta-mediated response to hypoxia, a model of transient ischemic attack, and examine the ability of anti inflammatory cytokines to modulate IL-1 beta- mediated central inflammatory processes in diabetes.