Journal
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
Volume 107, Issue 2, Pages 304-310Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbiomolbio.2011.07.013
Keywords
Insulin secretion; Pancreatic beta cell; ATP; Reactive oxygen species; Src
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Funding
- Ministry of Health, Labour, and Welfare of Japan
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- CREST of Japan Science and Technology Cooperation
- Grants-in-Aid for Scientific Research [23591308] Funding Source: KAKEN
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One of the characteristics of type 2 diabetes is that the insulin secretory response of beta 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 beta cells is reviewed. In beta 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 beta cells. (C) 2011 Elsevier Ltd. All rights reserved.
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