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

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.

NAD+: A key metabolic regulator with great therapeutic potential

“…21 Part of the reason for this discrepancy might relate to the fact that eNAMPT exists in different forms, with a dimeric form involved in NAD + biosynthesis, and a monomeric form of eNAMPT suggested to be a pathogenic factor in diabetes. 22 Similar disparate findings have emerged with NAD + precursor compounds. Studies employing intraperitoneal or oral delivery of exogenous NMN have reported rapid uptake into tissues in mice, 23,24 whereas another study suggested the possibility that NMN is first converted into NR for uptake into tissues.…”

“…Yet, other laboratories have failed to replicate eNAMPT‐mediated NAD biosynthesis or detect NMN or appreciable amounts of the NAMPT substrates ATP and 5‐phosphoribosyl 1‐pyrophosphate in the blood . Part of the reason for this discrepancy might relate to the fact that eNAMPT exists in different forms, with a dimeric form involved in NAD + biosynthesis, and a monomeric form of eNAMPT suggested to be a pathogenic factor in diabetes . Similar disparate findings have emerged with NAD + precursor compounds.…”

Can the skin make you fat? A role for the skin in regulating adipose tissue function and whole-body glucose and lipid homeostasis

“…In addition, a wide range of pro-inflammatory cytokines and chemokines, including TNF-, IL6, IL8, IL17, and IL1-, are also secreted from both keratinocytes and immune cells within the skin [39,40,55,57,58]. Importantly, such cytokines as well as many of the skin-derived proteins described above, have been separately shown to exert well described gluco-and lipo-regulatory effects on metabolic target tissues [35,46,[59][60][61][62][63]. This, together with the fact that skin expression and secretion of a number of these bioactive mediators are altered in psoriasis and ageing [64][65][66], provides a plausible link between skin inflammation, poor skin function and development of insulin resistance and T2D.…”

The Relationship between Plasma Visfatin/Nampt and Type 2 Diabetes, Obesity, Insulin Resistance, and Cardiovascular Disease

“…23 A very recent study in animal models of diabetes showed that the monomeric iso-form of eNampt (rather than the diameric iso-form) is responsible of diabetes and inflammation in animal models. 38 The authors showed that serum monomeric eNAMPT levels were elevated in HFDfed mouse models of diabetes, whilst eNAMPT-dimer levels were unchanged. Very interestingly, eNAMPT-monomer neutralisation in HFD-fed mice with anti-monomeric eNampt antibodies resulted in lower blood glucose levels, amelioration of impaired glucose tolerance and whole-body insulin resistance, improved pancreatic islet function, and reduced inflammation.…”

“…Very interestingly, eNAMPT-monomer neutralisation in HFD-fed mice with anti-monomeric eNampt antibodies resulted in lower blood glucose levels, amelioration of impaired glucose tolerance and whole-body insulin resistance, improved pancreatic islet function, and reduced inflammation. 38 These effects were maintained for at least 3 weeks post-treatment. On the other hand, eNAMPT-monomer administration induced a diabetic phenotype in mice, characterized by elevated blood glucose, IGT, impaired pancreatic insulin secretion and the presence of systemic and tissue inflammation, without changes in NAD levels.…”