Lipopolysaccharides Impair Insulin Gene Expression in Isolated Islets of Langerhans via Toll-Like Receptor-4 and NF-κB Signalling

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.

Association between Asp299Gly and Thr399Ile Polymorphisms in Toll-Like Receptor 4 Gene and Type 2 Diabetes Mellitus: Case-Control Study and Meta- Analysis

“…Furthermore, a recent study showed that treatment with LPS inhibits insulin gene expression in rat and human pancreatic beta-cells in a TLR4-dependent manner and via NF-κB signaling [45]. Importantly, the effects of LPS on the insulin gene in human islets were observed at concentrations similar to the circulating levels achieved during endotoxemia, suggesting that direct repression of the insulin gene might contribute to the metabolic disturbances associated with alterations of microbiota [45].…”

An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes

“…The underlying mechanism of this inhibition requires further investigations, though it has already been described that HERV-W-Env exerts its pathogenic effects through an interaction with the TLR4 receptor (35,36). From a T1D perspective, this mechanism appears relevant, as TLR4 is expressed by β cells (42)(43)(44). Moreover, the inhibition of insulin secretion following TLR4 stimulation has already been observed in human, rat, and mouse pancreatic β cells by using lipopolysaccharide (LPS), the prototypical ligand of TLR4 (42,43).…”

“…From a T1D perspective, this mechanism appears relevant, as TLR4 is expressed by β cells (42)(43)(44). Moreover, the inhibition of insulin secretion following TLR4 stimulation has already been observed in human, rat, and mouse pancreatic β cells by using lipopolysaccharide (LPS), the prototypical ligand of TLR4 (42,43). Inhibition appeared related to the repression of key transcription factors for β cell functions, PDX-1 and Maf-A, in a TLR4-dependent manner and via NF-κB signaling pathway (43).…”

Obese Patient-Derived Sera have Proinflammatory Effect

“…FFAs can activate the TLR4 receptors of adipocytes and macrophages, and the inflammatory effect of FFAs is blocked in TLR4-deficient cells [25]. In addition, lipopolysaccharide (LPS) inhibits beta-cell gene expression in a TLR4-dependent manner and via NF-κB signaling in pancreatic islets [26]. Inhibition of TLR4 reduces hypothalamic inflammation, accompanied by a reduction in hypothalamic resistance to leptin and improved insulin signal transduction in the liver [27].…”