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

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

doi:10.1007/s00125-016-4076-3

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

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

Nutritional Sciences

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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

Original language	English
Journal	Diabetologia
Volume	59
Issue number	11
Early online date	19 Aug 2016
DOIs	https://doi.org/10.1007/s00125-016-4076-3
Publication status	Published - Nov 2016

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eNAMPT-monomer plays an_KIESWICH_Accepted22July2016_GREEN AAMAccepted author manuscript, 1.68 MBLicence: Unspecified
Monomeric eNAMPT in the development of experimental diabetes in mice_KIESWICH_Firstonline19August2016_GOLD VoRFinal published version, 1.57 MBLicence: CC BY

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

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",

author = "Julius Kieswich and Sayers, {Sophie Rose} and Marta Silvestre and Steven harwood and Mohammad Yaqoob and Caton, {Paul William}",

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doi = "10.1007/s00125-016-4076-3",

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AU - Kieswich, Julius

AU - Sayers, Sophie Rose

AU - Silvestre, Marta

AU - harwood, Steven

AU - Yaqoob, Mohammad

AU - Caton, Paul William

PY - 2016/11

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N2 - 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

AB - 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

U2 - 10.1007/s00125-016-4076-3

DO - 10.1007/s00125-016-4076-3

M3 - Article

SN - 0012-186X

VL - 59

JO - Diabetologia

JF - Diabetologia

IS - 11

ER -

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

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