title: Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-κB signalling.
abstract: BACKGROUND
  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 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in islets.
  
  
  RESULTS
  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 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
  Our 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.
authors.affiliation: Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Quebec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Amyot
authors.forename: Meriem
authors.initials: M
authors.lastname: Semache
authors.forename: Mourad
authors.initials: M
authors.lastname: Ferdaoussi
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Fontés
authors.forename: Vincent
authors.initials: V
authors.lastname: Poitout
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012322:RNA Precursors; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein