Role of endogenous ROS production in impaired metabolism-secretion coupling of diabetic pancreatic β cells.

One of the characteristics of type 2 diabetes is that the insulin secretory response of β cells is selectively impaired to glucose. In the Goto-Kakizaki (GK) rat, a genetic model of type 2 diabetes mellitus, glucose-induced insulin secretion is selectively impaired due to deficient ATP production derived from impaired glucose metabolism. In addition, islets in GK rat and human type 2 diabetes are oxidatively stressed. In this issue, role of endogenous reactive oxygen species (ROS) production in impaired metabolism-secretion coupling of diabetic pancreatic β cells is reviewed. In β cells, ROS is endogenously produced by activation of Src, a non-receptor tyrosine kinase. Src inhibitors restore the impaired insulin release and impaired ATP elevation by reduction in ROS production in diabetic islets. Src is endogenously activated in diabetic islets, since the level of Src pY416 in GK islets is higher than that in control islets. In addition, exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, decreases Src pY416 and glucose-induced ROS production and ameliorates impaired ATP production dependently on Epac in GK islets. These results indicate that GLP-1 signaling regulates endogenous ROS production due to Src activation and that incretin has unique therapeutic effects on impaired glucose metabolism in diabetic β cells.