Back to Search
Start Over
Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment
- Source :
- Diabetologia, Kieswich, J, Sayers, S R, Silvestre, M, harwood, S, Yaqoob, M & Caton, P W 2016, ' Monomeric eNAMPT in the development of experimental diabetes in mice: a potential target for type 2 diabetes treatment ', Diabetologia, vol. 59, no. 11 . https://doi.org/10.1007/s00125-016-4076-3
- Publication Year :
- 2016
-
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. Electronic supplementary material The 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.
- Subjects :
- 0301 basic medicine
Male
Islet
medicine.medical_specialty
medicine.medical_treatment
Endocrinology, Diabetes and Metabolism
Nicotinamide phosphoribosyltransferase
030209 endocrinology & metabolism
Type 2 diabetes
Biology
In Vitro Techniques
Diet, High-Fat
Antibodies
Article
Proinflammatory cytokine
Cell Line
Diabetes Mellitus, Experimental
Impaired glucose tolerance
03 medical and health sciences
chemistry.chemical_compound
Islets of Langerhans
Mice
0302 clinical medicine
Insulin resistance
Diabetes mellitus
Internal medicine
medicine
Internal Medicine
Animals
Insulin
Extracellular nicotinamide phosphoribosyltransferase
eNAMPT
Pancreatic islet function
Nicotinamide Phosphoribosyltransferase
Inflammation
Reverse Transcriptase Polymerase Chain Reaction
medicine.disease
Lipid Metabolism
Mice, Inbred C57BL
Beta cell
030104 developmental biology
Endocrinology
chemistry
Diabetes Mellitus, Type 2
Liver
Insulin Resistance
Subjects
Details
- ISSN :
- 14320428
- Volume :
- 59
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Diabetologia
- Accession number :
- edsair.doi.dedup.....8100dac60d70e731b0b2250faec35972