Abstract
Aims/hypothesisSerum 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.MethodsTwo 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.ResultsSerum 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/interpretationWe 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-4076-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Type 2 diabetes is characterised by the presence of peripheral insulin resistance and pancreatic beta cell dysfunction [1]
High-fat feeding selectively induces the production and secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT)-monomer We first demonstrated that serum eNAMPT levels were elevated in diabetic high-fat diet (HFD)-fed mice (Fig. 1a)
Indicative of a selective diabetogenic function, eNAMPT-monomer protein levels were markedly elevated in serum (82.0 ± 1.9%; Fig. 1b, c) of HFD-fed mice compared with control diet (CON)-fed mice
Summary
Type 2 diabetes is characterised by the presence of peripheral insulin resistance and pancreatic beta cell dysfunction [1]. Determining the precise pathophysiological mechanisms responsible for these processes is essential for the development of novel therapeutics. Serum concentrations of extracellular nicotinamide phosphoribosyltransferase (eNAMPT; referred to as visfatin/pre-B cell colony-enhancing factor [PBEF]) are commonly elevated in type 2 diabetes patients [2], whilst raised eNAMPT levels strongly correlate with declining beta cell function [3]. A pathophysiological role is implied for eNAMPT in type 2 diabetes. Other studies have reported both insulin sensitising and beta cell protective effects of eNAMPT [4,5,6,7]. The precise relationship between elevated eNAMPT and type 2 diabetes remains unresolved
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
