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Cell Calcium. 2010 Aug-Sep;48(2-3):133-42. doi: 10.1016/j.ceca.2010.07.007. Epub 2010 Aug 25.

Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling.

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  • 1Department of Medicine, University of Virginia, Charlottesville, 22908, United States.

Abstract

In obesity and the early stages of type 2 diabetes (T2D), proinflammatory cytokines are mildly elevated in the systemic circulation. This low-grade systemic inflammation exposes pancreatic islets to these circulating cytokines at much lower levels than seen within the islet during insulitis. These low-dose effects have not been well described. We examined mouse islets treated overnight with a low-dose cytokine combination commonly associated with inflammation (TNF-alpha, IL-1 beta, and IFN-gamma). We then examined islet function primarily using intracellular calcium ([Ca(2+)](i)), a key component of insulin secretion and cytokine signaling. Cytokine-treated islets demonstrated several features that suggested dysfunction including excess [Ca(2+)](i) in low physiological glucose (3mM), reduced responses to glucose stimulation, and disrupted [Ca(2+)](i) oscillations. Interestingly, islets taken from young db/db mice showed similar disruptions in [Ca(2+)](i) dynamics as cytokine-treated islets. Additional studies of control islets showed that the cytokine-induced elevation in basal [Ca(2+)](i) was due to both greater calcium influx through L-type-calcium-channels and reduced endoplasmic reticulum (ER) calcium storage. Many of these cytokine-induced disruptions could be reproduced by SERCA blockade. Our data suggest that chronic low-grade inflammation produces circulating cytokine levels that are sufficient to induce beta-cell dysfunction and may play a contributing role in beta-cell failure in early T2D.

Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID:
20800281
[PubMed - indexed for MEDLINE]
PMCID:
PMC2948622
Free PMC Article

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