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- Title
Beta-Cell Recovery from Nitric Oxide-Mediated Damage: Role of AMPK.
- Authors
Salvatori, Alison S.; Corbett, John A.
- Abstract
Autoimmune diabetes is characterized by the selective destruction of insulin secreting pancreatic β-cells. Cytokines, such as IL-1, which are released during insulitis can directly induce β-cell dysfunction by a mechanism that is dependent on the expression of inducible nitric oxide synthase and the subsequent production of nitric oxide. β-cell dysfunction in response to nitric oxide is characterized by an inhibition of the mitochondrial enzyme aconitase, a decline in ATP content, and inhibition of glucose-stimulated insulin secretion. Importantly, β-cells have the capacity to recover from cytokine- and nitric oxide-mediated damage and this recovery pathway is dependent on new gene transcription and the activation of JNK. AMPK (5'-AMP-activated protein kinase) is a serine/threonine protein kinase that functions as a cellular energy sensor and is activated in response to a decline in ATP content. Since nitric oxide production in response to cytokines decreases cellular ATP levels by four fold, we hypothesize that AMPK may be activated in β-cells producing nitric oxide. The purpose of this study was to determine if nitric oxide activates AMPK in β-cells, and whether AMPK plays a role in β-cell recovery from nitric oxide-induced damage. We show that nitric oxide activates AMPK in β-cells as indicated by phosphorylation of the catalytic subunit of AMPK, and of the downstream target eIF2α. The phosphorylation of eIF2α is consistent with previous findings that nitric oxide inhibits protein synthesis in β-cells. Nitric oxide also enhances the expression of the catalytic subunits of AMPK and cytosolic inhibitor of apoptosis protein-2 (cIAP-2), in β-cells, cIAP-2 is a JNK-responsive, pro-survival gene. Expression of a dominant negative AMPK mutant attenuates RINm5F cell recovery from cytokine and nitric oxide-mediated damage, providing direct support for a role of AMPK in the recovery of β-cells from cytokine-mediated damage. These findings indicate that AMPK is activated by nitric oxide in β-cells and that AMPK participates in regulating the recovery of β-cells from cytokine-mediated damage. ADA-Funded Research
- Subjects
PANCREATIC beta cells; NITRIC oxide; PROTEIN kinases; ADENOSINE monophosphate; DIABETES; CYTOKINES
- Publication
Diabetes, 2007, Vol 56, pA510
- ISSN
0012-1797
- Publication type
Article