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Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment

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Julius Kieswich, Sophie Rose Sayers, Marta Silvestre, Steven harwood, Mohammad Yaqoob, Paul William Caton

Original languageEnglish
JournalDiabetologia
Volume59
Issue number11
Early online date19 Aug 2016
DOIs
E-pub ahead of print19 Aug 2016
PublishedNov 2016

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Abstract

Aims/Hypothesis Serum extra-cellular 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 monomer and dimer forms. eNAMPT-dimer exerts NADbiosynthetic activity. The role of eNAMPT-monomer is unclear but may exert NAD-independent proinflammatory effects. However studies of eNAMPT in type 2 diabetes have not distinguished between monomer and dimer forms. Since type 2 diabetes is characterised by chronic inflammation, we hypothesised a selective role for NAD-independent eNAMPT-monomer in type 2 diabetes. Methods Two models were used to examine the role of eNAMPT-monomer in type 2 diabetes; (A) diabetic high-fat fed mice (HFD; 10 weeks) were administered (I.P.) anti-eNAMPT-monomer antibody; (B) lean non-diabetic mice were administered recombinant eNAMPT-monomer daily (14 days; I.P.) Results Serum eNAMPT-monomer levels were elevated in diabetic HFD mice, whilst eNAMPT-dimer levels were unchanged. eNAMPT-monomer neutralization in HFD mice resulted in lowered blood glucose, amelioration of impaired glucose tolerance (IGT) and whole-body insulin resistance, improved pancreatic islet function and reduced inflammation. These effects were maintained at least 3 weeks post-dosing. eNAMPT-monomer administration induced a diabetic phenotype in mice, characterised by elevated blood glucose, IGT, impaired pancreatic insulin secretion and presence of systemic and tissue inflammation, without changes in NAD levels. Conclusions/Interpretations We demonstrate that elevation of eNAMPT-monomer plays an important role in the pathogenesis of diet-induced diabetes, via pro-inflammatory mechanisms. These data provide proof-of-concept evidence that eNAMPT-monomer represents a potential therapeutic target for type 2 diabetes

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