title: LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro.
abstract: Activation of inflammatory pathways is involved in the pathogenesis of type 2 diabetes mellitus. On the basis of its role in vascular inflammation and in metabolic disorders, we hypothesised that the TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) could be involved in the pathogenesis of type 2 diabetes mellitus.
  
  
  
  Plasma levels of LIGHT were measured in two cohorts of type 2 diabetes mellitus patients (191 Italian and 40 Norwegian). Human pancreatic islet cells and arterial endothelial cells were used to explore regulation and relevant effects of LIGHT in vitro.
  
  
  
  Our major findings were: (1) in both diabetic cohorts, plasma levels of LIGHT were significantly raised compared with sex- and age-matched healthy controls (n = 32); (2) enhanced release from activated platelets seems to be an important contributor to the raised LIGHT levels in type 2 diabetes mellitus; (3) in human pancreatic islet cells, inflammatory cytokines increased the release of LIGHT and upregulated mRNA and protein levels of the LIGHT receptors lymphotoxin β receptor (LTβR) and TNF receptor superfamily member 14 (HVEM/TNFRSF14); (4) in these cells, LIGHT attenuated the insulin release in response to high glucose at least partly via pro-apoptotic effects; and (5) in human arterial endothelial cells, glucose boosted inflammatory response to LIGHT, accompanied by an upregulation of mRNA levels of HVEM (also known as TNFRSF14) and LTβR (also known as LTBR).
  
  
  
  Our findings show that patients with type 2 diabetes mellitus are characterised by increased plasma LIGHT levels. Our in vitro findings suggest that LIGHT may contribute to the progression of type 2 diabetes mellitus by attenuating insulin secretion in pancreatic islet cells and by contributing to vascular inflammation.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway. bente.halvorsen@rr-research.no.|K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway. bente.halvorsen@rr-research.no.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. bente.halvorsen@rr-research.no.
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.affiliation: Center of Excellence on Aging, University of Chieti, Chieti, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Santilli
authors.affiliation: Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Section for Transplantation Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Hanne
authors.initials: H
authors.lastname: Scholz
authors.affiliation: Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Section for Transplantation Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Afaf
authors.initials: A
authors.lastname: Sahraoui
authors.affiliation: Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Hanne L
authors.initials: HL
authors.lastname: Gulseth
authors.affiliation: Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Wium
authors.affiliation: Center of Excellence on Aging, University of Chieti, Chieti, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Lattanzio
authors.affiliation: Center of Excellence on Aging, University of Chieti, Chieti, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Formoso
authors.affiliation: Center of Excellence on Aging, University of Chieti, Chieti, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Di Fulvio
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Kari
authors.initials: K
authors.lastname: Otterdal
authors.affiliation: Lipid Clinic, Oslo University Hospital Rikshospitalet, Oslo, Norway.|Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Retterstøl
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.|National Advisory Unit on Familial Hypercholesterolemia, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Holven
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ida
authors.initials: I
authors.lastname: Gregersen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Stavik
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Vigdis
authors.initials: V
authors.lastname: Bjerkeli
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Annika E
authors.initials: AE
authors.lastname: Michelsen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.|K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.affiliation: Center of Excellence on Aging, University of Chieti, Chieti, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Liani
authors.affiliation: Center of Excellence on Aging, University of Chieti, Chieti, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Davi
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0372, Oslo, Norway.|K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.|K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
mesh_terms: D000368:Aged; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism* / Q000503:physiopathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D053259:Lymphotoxin beta Receptor; D012333:RNA, Messenger; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14
keywords: Cytokines; Endothelial cells; Inflammation; Insulin; Islets; Type 2 diabetes