title: Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment.
abstract: Serum extracellular nicotinamide phosphoribosyltransferase (eNAMPT) concentrations are elevated in type 2 diabetes. However, the relationship between abnormally elevated serum eNAMPT and type 2 diabetes pathophysiology is unclear. eNAMPT circulates in functionally and structurally distinct monomeric and dimeric forms. Dimeric eNAMPT promotes NAD biosynthesis. The role of eNAMPT-monomer is unclear but it may have NAD-independent proinflammatory effects. However, studies of eNAMPT in type 2 diabetes have not distinguished between monomeric and dimeric forms. Since type 2 diabetes is characterised by chronic inflammation, we hypothesised a selective NAD-independent role for eNAMPT-monomer in type 2 diabetes.
  
  
  
  Two mouse models were used to examine the role of eNAMPT-monomer in type 2 diabetes; (1) a mouse model of diabetes fed a high-fat diet (HFD) for 10 weeks received i.p. injections with an anti-monomeric-eNAMPT antibody; and (2) lean non-diabetic mice received i.p. injections with recombinant monomeric eNAMPT daily for 14 days.
  
  
  
  Serum monomeric eNAMPT levels were elevated in HFD-fed mouse models of diabetes, whilst eNAMPT-dimer levels were unchanged. eNAMPT-monomer neutralisation in HFD-fed mice resulted in lower blood glucose levels, amelioration of impaired glucose tolerance (IGT) and whole-body insulin resistance, improved pancreatic islet function, and reduced inflammation. These effects were maintained for at least 3 weeks post-treatment. eNAMPT-monomer administration induced a diabetic phenotype in mice, characterised by elevated blood glucose, IGT, impaired pancreatic insulin secretion and the presence of systemic and tissue inflammation, without changes in NAD levels.
  
  
  
  We demonstrate that elevation of monomeric-eNAMPT plays an important role in the pathogenesis of diet-induced diabetes via proinflammatory mechanisms. These data provide proof-of-concept evidence that the eNAMPT-monomer represents a potential therapeutic target for type 2 diabetes.
authors.affiliation: Translational Medicine and Therapeutics, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Julius
authors.initials: J
authors.lastname: Kieswich
authors.affiliation: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London, Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Sayers
authors.affiliation: Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.|Human Nutrition Unit, University of Auckland, Auckland, New Zealand.
authors.forename: Marta F
authors.initials: MF
authors.lastname: Silvestre
authors.affiliation: Translational Medicine and Therapeutics, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Harwood
authors.affiliation: Translational Medicine and Therapeutics, William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Yaqoob
authors.affiliation: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King's College London, Hodgkin Building, Guy's Campus, London, SE1 1UL, UK. paul.w.caton@kcl.ac.uk.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Caton
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000906:Antibodies; D007328:Insulin; D054409:Nicotinamide Phosphoribosyltransferase
keywords: Beta cell; Extracellular nicotinamide phosphoribosyltransferase; Inflammation; Islet; Type 2 diabetes; eNAMPT