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

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. 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 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/SIGNIFICANCE: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

Food consumption and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes: a nested case-control design

BACKGROUND: Evidence for the role of food consumption during childhood in the development of β cell autoimmunity is scarce and fragmentary. OBJECTIVE: We set out to study the associations of longitudinal food consumption in children with the development of advanced β cell autoimmunity. DESIGN: Children with advanced β cell autoimmunity (n = 232) (ie, with repeated positivity for antibodies against islet cells) together with positivity for at least one of the other 3 antibodies analyzed or clinical type 1 diabetes were identified from a prospective birth cohort of 6069 infants with HLA-DQB1-conferred susceptibility to type 1 diabetes who were born in 1996-2004, with the longest follow-up to the age of 11 y. Repeated 3-d food records were completed by the families and daycare personnel. Diabetes-associated autoantibodies and diets were measured at 3-12-mo intervals. Four control subjects, who were matched for birth date, sex, area, and genetic risk, were randomly selected for each case. RESULTS: In the main food groups, only intakes of cow-milk products (OR: 1.05; 95% CI: 1.00, 1.10) and fruit and berry juices (OR: 1.09; 95% CI: 1.02, 1.12) were significantly, although marginally, associated with advanced β cell autoimmunity. The consumption of fresh milk products and cow milk-based infant formulas was related to the endpoint, whereas no evidence was shown for consumption of sour milk products and cheese. The intake of fat from all milk products and protein from fresh milk products was associated with risk of advanced β cell autoimmunity. CONCLUSION: Intakes of cow milk and fruit and berry juices could be related to the development of advanced β cell autoimmunity. This trial was registered at clinicaltrials.gov as number NCT00223613