BLX‐1002 restores glucose sensitivity and enhances insulin secretion stimulated by GLP‐1 and sulfonylurea in type 2 diabetic pancreatic islets

BLX-1002 is a novel thiazolidinedione with no peroxisome proliferator-activated receptor (PPAR) activity that has been shown to improve glycemia in type 2 diabetes without weight gain. We previously found that BLX-1002 selectively augments glucose-sensitive (but not basal) insulin secretion in normal mouse β-cells. We have now extended these observations to other insulin secretagogues and to diabetic rat islets. To this end, dynamics of insulin secretion stimulated by glucose, GLP-1, and the sulfonylurea tolbutamide were examined in pancreatic islets from nondiabetic Wistar and type 2 diabetic Goto-Kakizaki rats ex vivo. BLX-1002 restored normal glucose-sensitive insulin secretion in otherwise "glucose-blind" islets from GK rats, but did not affect basal or glucose-stimulated secretion in normal Wistar rat islets. The stimulatory effect of BLX-1002 on insulin secretion at high glucose required Ca(2+) and involved phosphatidylinositol 3-kinase (PI3K) activity. Consistent with its effects on insulin secretion, BLX-1002 also augmented insulin secretion and cytoplasmic-free Ca(2+) concentrations ([Ca(2+)]i) stimulated by high glucose, GLP-1, and tolbutamide in islets from GK, but not Wistar, rats. The inactive analog BLX-1237 had no effects. In conclusion, our findings suggest that BLX-1002 potentiates insulin secretion by different stimuli in diabetic β-cells only, in a Ca(2+)-dependent manner and involving PI3K.