Glycemic Variability Affects Ischemia-Induced Angiogenesis In Diabetic Mice

Overview & Synopsis

The aim of this study was to investigate the role of glycemic variability (GV) on diabetic vascular complications and to explore the molecular pathways modulated by glycemic "swings".We performed a murine model. 30 diabetic mice received once daily basal insulin administration plus 2 oral bolus of glucose solution (GV group, V) and 30 diabetic mice received once daily basal insulin plus 2 oral bolus of saline solution (stable hyperglycemia group, S) for a period of 30 days. Glycemia was measured 8 times daily to detect GV. Finally, post-ischemic vascularization, induced by hindlimb ischemia 30 days after diabetes onset, was evaluated.We found that GV was significantly different between S and V groups, whereas no significant difference of the mean glycemic values was detected. Laser Doppler perfusion imaging and histological analysis revealed that the ischemia-induced angiogenesis was significantly impaired in V mice compared to S group, after ischemic injury. In addition, immunostaining and western blot analyses revealed that impaired angiogenic response in V mice occurred in association with reduced VEGF production and decreased eNOS and Akt phosphorylation.In conclusion, we describe a murine model of GV. GV causes an impairment of ischemia-induced angiogenesis in diabetes, likely to be independent of changes in average blood glucose levels, and this impaired collateral vessel formation is associated with an alteration of the VEGF pathway.