title: Increased expression of toll-like receptor 4 and inflammatory cytokines, interleukin-6 in particular, in islets from a mouse model of obesity and type 2 diabetes.
abstract: Toll-like receptor 4 (TLR4) has received much attention in the recent years due to its role in development of insulin resistance in type 2 diabetes mellitus. Its expression is elevated in fat and muscle from insulin-resistant mice. Several cells of the pancreatic islets, including β-cells and resident macrophages, express TLR4. Our hypothesis is that expression of TLR4 and downstream signalling molecules in islets increases during progression of type 2 diabetes, thereby contributing to β-cell damage. We investigated the hypothesis in the db/db mouse. Islets from male db/db (4, 8 and 15 weeks old) and control db/+ (4 and 15 weeks old) mice were examined for mRNA expression of TLR4 and selected cytokines using qPCR. In addition, cytokine secretion from islets was quantified. TLR4 is expressed in islets from lean and obese mice, displaying a 7.4-fold higher level in 15 weeks old db/db relative to age-matched control (p < 0.01). During progression of clinical type 2 diabetes manifested by hyperglycaemia, TLR4 expression increases 5.6-fold in islets from 15 weeks compared with 4 weeks old db/db mice (p < 0.01). Furthermore, both protein and mRNA levels of all cytokines examined increased. In particular, expression of IL-6 increased with 37 fold. Expression of TLR4 in db/db mouse islets increased in parallel with hyperglycaemia. A similar increase in expression and secretion of TNFα, IL-1 and IL-6 was observed. Our results demonstrate that, in addition to its contribution to insulin resistance, TLR4 might also play a role in β-cell dysfunction in type 2 diabetes.
authors.affiliation: Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Ladefoged
authors.forename: Karsten
authors.initials: K
authors.lastname: Buschard
authors.forename: Ann Maria Kruse
authors.initials: AM
authors.lastname: Hansen
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse