Cellular Signalling, 2013, 01, 2348─2361

In vivo activating tranion factor 3 silencing ameliorates the AMPK compensatory effects for ER stress-mediated β-cell dysfunction during the progression of type-2 diabetes.

JiYeon Kim, Keun Jae Park, Gyu Hee Kim, Eun Ae Jeong, Dae Yeon Lee, Seong Su Lee, Dae Jin Kim, Gu Seob Roh, Jihyun Song, Sung Hwan Ki, Won-Ho Kim

Abstract

In obese Zucker diabetic fatty (ZDF) rats, ER stress is associated with insulin resistance and pancreatic β-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 β-cell dysfunction during the end-stage progression of hyperglycemia in ZDF rats. The impaired glucose metabolism and β-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 β-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 β-cell dysfunction. Moreover, knockdown of ATF3 by delivery of in vivo-jetPEI ATF3 siRNA attenuated ER stress-mediated β-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 β-cell dysfunction and the development of type-2 diabetes and could be a potential therapeutic target in treating type-2 diabetes.

• ISBN or ISSN: 0898-6568

• 본 연구는 질병관리본부 연구개발과제(과제번호 2011-NG64001-00) 연구비를 지원받아 수행되었습니다.
• This research was supported by a fund(code 2011-NG64001-00) by Research of Korea Centers for Disease Control and Prevention.