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Diabetologia
Published in: Diabetologia 11/2016

Open Access 01-11-2016 | Article

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

Authors: Julius Kieswich, Sophie R. Sayers, Marta F. Silvestre, Steven M. Harwood, Muhammad M. Yaqoob, Paul W. Caton

Published in: Diabetologia | Issue 11/2016

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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.
Appendix
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Metadata
Title
Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment
Authors
Julius Kieswich
Sophie R. Sayers
Marta F. Silvestre
Steven M. Harwood
Muhammad M. Yaqoob
Paul W. Caton
Publication date
01-11-2016
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 11/2016
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-016-4076-3

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