Dataset Information

Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-?B signalling.

ABSTRACT:

Background

Type 2 diabetes is characterized by pancreatic ?-cell dysfunction and is associated with low-grade inflammation. Recent observations suggest that the signalling cascade activated by lipopolysaccharides (LPS) binding to Toll-Like Receptor 4 (TLR4) exerts deleterious effects on pancreatic ?-cell function; however, the molecular mechanisms of these effects are incompletely understood. In this study, we tested the hypothesis that LPS alters insulin gene expression via TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) in islets.

Methodology/principal findings

A 24-h exposure of isolated human, rat and mouse islets of Langerhans to LPS dose-dependently reduced insulin gene expression. This was associated in mouse and rat islets with decreased mRNA expression of pancreas-duodenum homebox-1 (PDX-1) and mammalian homologue of avian MafA/l-Maf (MafA). Accordingly, LPS exposure also decreased glucose-induced insulin secretion. LPS repression of insulin, PDX-1 and MafA expression, as well as its inhibition of insulin secretion, were not observed in islets from TLR4-deficient mice. LPS inhibition of ?-cell gene expression in rat islets was prevented by inhibition of the NF-?B pathway, but not the p38 mitogen-activated protein kinase (p38 MAPK) pathway.

Conclusions/significance

Our findings demonstrate that LPS inhibit ?-cell gene expression in a TLR4-dependent manner and via NF-?B signaling in pancreatic islets, suggesting a novel mechanism by which the gut microbiota might affect pancreatic ?-cell function.

SUBMITTER: Amyot J

PROVIDER: S-EPMC3338606 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-κB signalling.

Amyot Julie J Semache Meriem M Ferdaoussi Mourad M Fontés Ghislaine G Poitout Vincent V

PloS one 20120427 4

<h4>Background</h4>Type 2 diabetes is characterized by pancreatic β-cell dysfunction and is associated with low-grade inflammation. Recent observations suggest that the signalling cascade activated by lipopolysaccharides (LPS) binding to Toll-Like Receptor 4 (TLR4) exerts deleterious effects on pancreatic β-cell function; however, the molecular mechanisms of these effects are incompletely understood. In this study, we tested the hypothesis that LPS alters insulin gene expression via TLR4 and nuc ...[more]

PMID: 22558381

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