Abstract
BackgroundType 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 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in islets.Methodology/Principal FindingsA 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 β-cell gene expression in rat islets was prevented by inhibition of the NF-κB pathway, but not the p38 mitogen-activated protein kinase (p38 MAPK) pathway.Conclusions/SignificanceOur findings demonstrate that LPS inhibit β-cell gene expression in a TLR4-dependent manner and via NF-κB signaling in pancreatic islets, suggesting a novel mechanism by which the gut microbiota might affect pancreatic β-cell function.
Highlights
The prevalence of diabetes mellitus is rising across the world, closely associated with a dramatic increase in obesity rates
Conclusions/Significance: Our findings demonstrate that LPS inhibit b-cell gene expression in a Toll-Like Receptor 4 (TLR4)-dependent manner and via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling in pancreatic islets, suggesting a novel mechanism by which the gut microbiota might affect pancreatic b-cell function
First we examined the effects of LPS on insulin gene expression in isolated islets
Summary
The prevalence of diabetes mellitus is rising across the world, closely associated with a dramatic increase in obesity rates. Type 2 diabetes (T2D) is characterized by defective insulin secretion from the pancreatic b-cell and diminished insulin sensitivity in peripheral tissues. Circulating levels of several inflammatory mediators such as acute-phase protein, cytokines and markers of endothelial activation are elevated in T2D patients (reviewed in [2]). Type 2 diabetes is characterized by pancreatic b-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 b-cell function; the molecular mechanisms of these effects are incompletely understood. We tested the hypothesis that LPS alters insulin gene expression via TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in islets
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