AMP-activated Protein Kinase Attenuates Nitric Oxide-induced β-Cell Death*
- Gordon P. Meares‡,1,
- Katherine J. Hughes‡,
- Kimberly F. Jaimes‡,
- Alison S. Salvatori§,
- Christopher J. Rhodes¶ and
- John A. Corbett‡,2
- From ‡Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and the Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, Alabama 35294,
- the §Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University, St. Louis, Missouri 63401, and
- the ¶Kovler Diabetes Center, Department of Medicine, University of Chicago, Chicago, Illinois 60637
- 1 To whom correspondence may be addressed: University of Alabama at Birmingham, SHEL 1271A, 1825 University Blvd., Birmingham, Al 35294. E-mail: mearegp{at}uab.edu.
- 2 To whom correspondence may be addressed: University of Alabama at Birmingham, SHEL 1271A, 1825 University Blvd., Birmingham, Al 35294. E-mail: corbettj{at}uab.edu.
Abstract
During the initial autoimmune response in type 1 diabetes, islets are exposed to a damaging mix of pro-inflammatory molecules that stimulate the production of nitric oxide by β-cells. Nitric oxide causes extensive but reversible cellular damage. In response to nitric oxide, the cell activates pathways for functional recovery and adaptation as well as pathways that direct β-cell death. The molecular events that dictate cellular fate following nitric oxide-induced damage are currently unknown. In this study, we provide evidence that AMPK plays a primary role controlling the response of β-cells to nitric oxide-induced damage. AMPK is transiently activated by nitric oxide in insulinoma cells and rat islets following IL-1 treatment or by the exogenous addition of nitric oxide. Active AMPK promotes the functional recovery of β-cell oxidative metabolism and abrogates the induction of pathways that mediate cell death such as caspase-3 activation following exposure to nitric oxide. Overall, these data show that nitric oxide activates AMPK and that active AMPK suppresses apoptotic signaling allowing the β-cell to recover from nitric oxide-mediated cellular stress.
- Cell/Apoptosis
- Cytokines/Interleukins
- Diseases/Diabetes
- Enzymes/Kinase
- Hormones/Insulin
- Radicals
- Signal Transduction
- Signal Transduction/Protein Kinases
- AMP-activated Kinase (AMPK)
- Nitric Oxide
Footnotes
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↵* This work was supported, in whole or in part, by the National Institutes of Health-UAB program in Immunology Training Grant T32AI007051-31A1 (to G. P. M.) and Grants R01-DK52194 and AI 44458 (to J. A. C.).
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↵4 J. A. Corbett, unpublished observation.
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↵3 The abbreviations used are:
- IL
- interleukin
- AMPK
- AMP-activated protein kinase
- AICAR
- 5-aminoimidazole-4-carboxyamide ribonucleoside
- ACC
- acetyl-CoA carboxylase
- DEANO
- (Z)-1(N,N-diethylamino) diazen-1-ium-1,2-diolate
- NMMA
- NG-monomethyl-l-arginine
- TNFα
- tumor necrosis factor α
- INFγ
- interferon γ
- iNOS
- inducible nitric-oxide synthase
- eIF2α
- eukaryotic initiation factor 2α
- HSP
- heat shock protein
- CaMKK
- calmodulin-dependent protein kinase kinase
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- GADD45
- growth arrest and DNA damage-inducible gene 45
- PGC1α
- peroxisome proliferator-activated receptor-gamma coactivator 1α
- PUMA
- p53-upregulated modulator of apoptosis
- CHOP
- C/EBP-homologous protein
- PARP
- poly(ADP-ribose) polymerase
- TUNEL
- terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
- DAPI
- 4′,6-diamidino-2-phenylindole
- CHAPS
- 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
- ANOVA
- analysis of variance
- WT
- wild type
- GFP
- green fluorescent protein.
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- Received July 21, 2009.
- Revision received November 20, 2009.
- © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
