Objectives To investigate the possible role of PI3k/Akt/GSK-3 signalling pathway in the pathogenesis of endothelial cells injury and oxidative stress induced by high glucose fluctuation in type 2 diabetes mellitus rats.

Methods 80 Sprague-Dawley rats, weighting 180-220 g, were obtained and housed according to the guidelines for laboratory animals approved by Beijing Experimental Animal Management Center. After 2 weeks of adaptive feeding, 10 rats were randomly selected as control group. The other 70 rats were switched from normal rodent diet to a high fat and high caloric laboratory chow. After 6-week of high fat and high caloric diet, rats were received only one intraperitoneal injection of a small dose of streptozotocin (STZ, 35 mg/kg) after feeding with normal rodent diet for 2 weeks. During the 10th week, fasting blood glucose (FBG) levels of rats were measured every morning by collecting blood samples from their caudal veins, meanwhile fasting blood glucose coefficient of variation (FBG-CV = inter-day blood glucose means/standard deviation) were calculated. The blood glucose levels of rats higher than 16.7mmol/L were thought to be successful T2DM diabetes. The normal control rats performed the same process at the same time, and FBG-CV was calculated as well. Rats with higher FBG-CV value of diabetes were divided into fluctuant high blood glucose groups, the others were steady high blood glucose group (SHG). There were 35 rats in fluctuant high blood glucose group, 15 rats in SHG group at last. Then the FHG rats were divided into 3 groups according to blood glucose levels and FBG-CV valued: Metformin Hydrochloride control group (MH), α-LA group (α-LA) and fluctuant high blood glucose control group (FHG), rats in which were received MH 300 mg/kg, α-LA 100 mg/kg and PBS per gavage for 8 wks respectively. All rats were fed with high caloric laboratory chow except normal control rats.

Results SOD level was decreased obviously, while MDA level increased in FHG rats, along with phosphorylation levels of Akt (Ser473) and GSK-3β (Ser9) were decreased significantly, compared with (P < 0.01 or P < 0.05). In addition, similar to Metformin Hydrochloride, (±)-α-Lipoic acid represented a robust protective influence on endothelial injury and oxidative stress by alleviating oxidative injury and improving phosphorylation levels of Akt and GSK-3β.

Conclusions These data established that high glucose fluctuation facilitate endothelial oxidative stress and hyperglycemia-impaired PI3k/Akt/GSK-3β signaling may promote endothelial injury in diabetes. PI3k/Akt/GSK-3β signalling activation plays a protective role in endothelial injury induced by high blood glucose fluctuation. Up-regulation of PI3k/Akt/GSK-3β signalling may provide us a potential target for prophylaxis and treatment of diabetes and its vascular complications.