title: Glucolipotoxicity initiates pancreatic β-cell death through TNFR5/CD40-mediated STAT1 and NF-κB activation.
abstract: Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis is associated with, and exacerbated by, obesity and the concomitant-elevated free fatty acid concentrations typically found in these patients. Hyperglycaemia and hyperlipidaemia together contribute to a decline in insulin-producing β-cell mass through activation of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-κB and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF-κB and STAT1 activation is currently poorly defined. Using high-density microarray analysis of the β-cell transcritptome, we have identified those genes and proteins most sensitive to glucose and fatty acid environment. Our data show that of those potentially able to activate STAT1 or NF-κB pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-κB activity in β-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-κB activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death.
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Marta
authors: M
authors: Bagnati
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Babatunji W
authors: BW
authors: Ogunkolade
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Catriona
authors: C
authors: Marshall
authors: Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK.
authors: Carmen
authors: C
authors: Tucci
authors: Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK.
authors: Katie
authors: K
authors: Hanna
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Tania A
authors: TA
authors: Jones
authors: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors: Marco
authors: M
authors: Bugliani
authors: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College, London, UK.
authors: Belinda
authors: B
authors: Nedjai
authors: Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK.
authors: Paul W
authors: PW
authors: Caton
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Julius
authors: J
authors: Kieswich
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Muhammed M
authors: MM
authors: Yaqoob
authors: Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK.
authors: Graham R
authors: GR
authors: Ball
authors: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors: Piero
authors: P
authors: Marchetti
authors: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors: Graham A
authors: GA
authors: Hitman
authors: Interdisciplinary Biomedical Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK.
authors: Mark D
authors: MD
authors: Turner
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008055:Lipids / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D019013:CD40 Antigens; D008055:Lipids; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D005947:Glucose