Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate glucose-dependent insulin secretion. The GLP-1 receptor agonist, exendin-4, has similar properties to GLP-1 and is currently in clinical use for type 2 diabetes mellitus. As GLP-1 and exendin-4 confer cardioprotection after myocardial infarction, this study was designed to assess the neuroprotective effects of exendin-4 against cerebral ischemia–reperfusion injury. Mice received a transvenous injection of exendin-4, after a 60-minute focal cerebral ischemia. Exendin-4-treated vehicle and sham groups were evaluated for infarct volume, neurologic deficit score, various physiologic parameters, and immunohistochemical analyses at several time points after ischemia. Exendin-4 treatment significantly reduced infarct volume and improved functional deficit. It also significantly suppressed oxidative stress, inflammatory response, and cell death after reperfusion. Furthermore, intracellular cyclic AMP (cAMP) levels were slightly higher in the exendin-4 group than in the vehicle group. No serial changes were noted in insulin and glucose levels in both groups. This study suggested that exendin-4 provides neuroprotection against ischemic injury and that this action is probably mediated through increased intracellular cAMP levels. Exendin-4 is potentially useful in the treatment of acute ischemic stroke.

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Aim:Prediabetes is an independent risk factor for future stroke. However, no effective treatment has yet been established for the recurrence of stroke in patients with prediabetes. Here we investigated the effects of pioglitazone, a potent peroxisome proliferator-activated receptor-gamma agonist, for the reduction of recurrent stroke in patients with prediabetes. Methods: Participants were patients who had a symptomatic ischemic stroke or transient ischemic attack (TIA) without a history of type 2 diabetes mellitus and who were diagnosed to have IGT or newly diagnosed diabetes by a 75-g oral glucose tolerance test. These patients were randomized to either receive or not receive pioglitazone. The primary endpoint was a recurrence of ischemic stroke. Results: A total of 120 patients were enrolled in the study. Sixty-three patients received pioglitazone and 57 were enrolled in the control group that did not receive pioglitazone. The majority of patients (68.3%) were prescribed 15 mg of pioglitazone, while the remaining patients (31.7%) were treated with 30 mg of pioglitazone. Over a median follow-up period of 2.8 years, treatment with pioglitazone was found to be associated with a lower rate of the primary endpoint (recurrence of stroke) than that observed in the control group [event rate 4.8% pioglitazone vs 10.5% control, hazard ratio 0.62, 95% confidence interval 0.13 -2.35, p 0.49]. However, differences were not statistically significant. Conclusions: While this study was too underpowered to determine the effect of pioglitazone, the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes. J Atheroscler Thromb, 2015; 22: 1305-1316.

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