AMP-activated protein kinase attenuates nitric oxide-induced beta-cell death.
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 beta-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 beta-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 beta-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 beta-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 beta-cell to recover from nitric oxide-mediated cellular stress.
Meares
Gordon P
GP
Department of Medicine, Division of Endocrinology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Hughes
Katherine J
KJ
Jaimes
Kimberly F
KF
Salvatori
Alison S
AS
Rhodes
Christopher J
CJ
Corbett
John A
JA
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D019070:Cell Lineage; D020552:Comet Assay; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007340:Insulinoma; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
D007375:Interleukin-1; D009573:Nitrites; D009569:Nitric Oxide; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D000154:Aconitate Hydratase