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Diabetologia ; 59(11): 2477-2486, 2016 11.
Article in English | MEDLINE | ID: mdl-27541013

ABSTRACT

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.


Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Nicotinamide Phosphoribosyltransferase/metabolism , Animals , Antibodies/therapeutic use , Cell Line , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diet, High-Fat/adverse effects , In Vitro Techniques , Insulin/metabolism , Insulin Resistance/physiology , Islets of Langerhans/metabolism , Lipid Metabolism/drug effects , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Nicotinamide Phosphoribosyltransferase/blood , Nicotinamide Phosphoribosyltransferase/genetics , Reverse Transcriptase Polymerase Chain Reaction
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