Journal
CELLULAR SIGNALLING
Volume 25, Issue 12, Pages 2348-2361Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2013.07.028
Keywords
Type 2 diabetes; Pancreatic beta-cells; ER stress; AMPK; ATF3; In vivo knockdown
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Funding
- Korean National Institutes of Health [4845-302-210-13]
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In obese Zucker diabetic fatty (ZDF) rats, ER stress is associated with insulin resistance and pancreatic beta-cell dysfunction: however the exact mechanisms by which ER stress drives type-2 diabetes remain uncertain. Here, we investigated the role of ATF3 on the preventive regulation of AMPK against ER stress-mediated beta-cell dysfunction during the end-stage progression of hyperglycemia in ZDF rats. The impaired glucose metabolism and beta-cell dysfunction were significantly increased in late-diabetic phase 19-week-old ZDF rats. Although AMPK phosphorylation reduced in 6- and 12-week-old ZDF rats was remarkably increased at 19 weeks, the increases of lipogenice genes, ATF3, and ER stress or ROS-mediated beta-cell dysfunction were still remained, which were attenuated by in vivo-injection of chemical chaperon tauroursodeoxycholate (TUDCA), chronic AICAR, or antioxidants. ATF3 did not directly affect AMPK phosphorylation, but counteracts the preventive effects of AMPK for high glucose-induced beta-cell dysfunction. Moreover, knockdown of ATF3 by delivery of in vivo-jetPEI ATF3 siRNA attenuated ER stress-mediated beta-cell dysfunction and enhanced the beneficial effect of AICAR. Our data suggest that ATF3 may play as a counteracting regulator of AMPK and thus promote beta-cell dysfunction and the development of type-2 diabetes and could be a potential therapeutic target in treating type-2 diabetes. (C) 2013 Elsevier Inc. All rights reserved.
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