AICAR potentiates ROS production induced by chronic high glucose: Roles of AMPK in pancreatic β-cell apoptosis
- Authors
- Kim, Won-Ho; Lee, June Woo; Suh, Young Ho; Lee, Hyun Jung; Lee, Seung Hee; Oh, Yeo Kyoung; Gao, Bin; Jung, Myeong Ho
- Issue Date
- 2007
- Keywords
- AICAR; AMPK; Apoptosis; Glucokinase; High glucose; Type 2 diabetes
- Citation
- Cellular Signalling, v.19, no.4, pp 791 - 805
- Pages
- 15
- Journal Title
- Cellular Signalling
- Volume
- 19
- Number
- 4
- Start Page
- 791
- End Page
- 805
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/65404
- DOI
- 10.1016/j.cellsig.2006.10.004
- ISSN
- 0898-6568
1873-3913
- Abstract
- We previously demonstrated that chronic high glucose (33.3 mM) induced β-cell dysfunction and apoptosis through glucokinase (GCK) downregulation, but the exact mechanisms involved remain unclear. Here, we show that prolonged exposure of 5-aminoimidazole-4-carboxamide (AICA)-riboside potentiated apoptosis induced by high glucose in MIN6N8 pancreatic β-cells, correlating with enhanced GCK downregulation and decreased production of ATP and insulin. These events are potentiated in AMPK-overexpressing cells, but are prevented in cells transfected with mutant dominant-negative AMPK (AMPK-K45R). Furthermore, AMPK activation increases production of reactive oxygen species (ROS) and loss of mitochondria membrane potential induced by high glucose, which is significantly inhibited by treatment with compound C or by AMPK-K45R overexpression. Overexpression of GCK prevents apoptosis; decreased cellular ATP and insulin secretion, and ROS production enhanced by AICAR, but does not affect AMPK activation. Similar results are obtained using isolated primary islet cells. Collectively, these data demonstrate that AMPK activation potentiates β-cell apoptosis induced by chronic high glucose through augmented GCK downregulation mediated by enhanced ROS production. © 2006 Elsevier Inc. All rights reserved.
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