Background and Purpose-Stroke and heart disease are the most serious complications of diabetes accounting for Ͼ65% of mortality among diabetics. Although intensive insulin therapy has significantly improved the prognosis of diabetes and its complications, it is associated with an elevated risk of recurrent hypoglycemia (RH). We tested the hypothesis that RH exacerbates cerebral ischemic damage in a rodent model of diabetes. Method-We determined the extent of neuronal death in CA1 hippocampus after global cerebral ischemia in control and streptozotocin-induced diabetic rats. Diabetic animals included an insulin-treated streptozotocin-diabetic (ITD) group and a group of ITD rats exposed also to 10 episodes of hypoglycemia (ITDϩrecurrent hypoglycemia: RH). Hypoglycemia (55 to 65 mg/dL blood glucose) was induced twice daily for 5 consecutive days. Results-As expected, uncontrolled diabetes (streptozotocin-diabetes, untreated animals) resulted in a 70% increase in ischemic damage as compared with the control group. Insulin treatment was able to lower ischemic damage by 64% as compared with the diabetic group. However, ITDϩRH rats had 44% more damage when compared with the ITD group. We also observed that free radical release from mitochondria is increased in ITDϩRH rats. Conclusions-This is the first report on the impact of RH in exacerbating cerebral ischemic damage in diabetic animals.Our results suggest that increased free radical release from mitochondria may be responsible for observed increased ischemic damage in ITDϩRH rats. RH thus may be an unexplored but important factor responsible for increased ischemic damage in diabetes. (Stroke. 2011;42:1404-1411.)Key Words: brain ischemia Ⅲ cardiac arrest Ⅲ diabetes Ⅲ free radicals Ⅲ glucose Ⅲ mitochondria Ⅲ stroke D iabetes is a devastating disease of epidemic proportions. It is estimated that 220 million patients are affected by diabetes worldwide. 1 Stroke and heart disease are the most serious complications of diabetes, because they account for approximately 65% of mortality among diabetics. 2 Epidemiological studies suggest that long-term diabetes increases the risk of cerebral ischemia as well as cardiovascular disease by 2 to 4 times as compared with the nondiabetic population. [3][4][5] The incidence of cerebral ischemia is greater in patients with Type 2 diabetes mellitus than Type 1 diabetes mellitus (T1DM). 3 Furthermore, cerebral infarction after ischemia is more extensive and common in diabetics, who also display slower recovery and worse survival rates than nondiabetic subjects. 6 Animal models corroborate these clinical observations and provide mechanistic insights into the pathophysiology of the effect of diabetes on cerebral ischemia. 7,8 It has been recognized that a high plasma glucose level is a key factor for the poor outcome observed after cerebral ischemia in diabetics. 9 Attaining tight glycemic control is a desirable goal for both patients with T1DM and Type 2 diabetes mellitus. Aggressive therapeutic interventions able to normalize glycohemog...