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

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 di...

Full description

Saved in:

Bibliographic Details
Published in:	Diabetologia Vol. 59; no. 11; pp. 2477 - 2486
Main Authors:	Kieswich, Julius, Sayers, Sophie R., Silvestre, Marta F., Harwood, Steven M., Yaqoob, Muhammad M., Caton, Paul W.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-11-2016 Springer Nature B.V
Subjects:	Animals Antibodies Antibodies - therapeutic use Cell Line Diabetes Diabetes Mellitus, Experimental - blood Diabetes Mellitus, Experimental - drug therapy Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Type 2 - blood Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Diet Diet, High-Fat - adverse effects Glucose Human Physiology In Vitro Techniques Inflammation Insulin - metabolism Insulin resistance Insulin Resistance - physiology Internal Medicine Islets of Langerhans - metabolism Lipid Metabolism - drug effects Liver - drug effects Liver - metabolism Male Medicine Medicine & Public Health Metabolic Diseases Mice Mice, Inbred C57BL Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors Nicotinamide Phosphoribosyltransferase - blood Nicotinamide Phosphoribosyltransferase - genetics Nicotinamide Phosphoribosyltransferase - metabolism Nutrition research Pathophysiology Reverse Transcriptase Polymerase Chain Reaction United Kingdom > UK United States > US Type 2 diabetes eNAMPT Inflammation Extracellular nicotinamide phosphoribosyltransferase Islet Beta cell
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0012-186X 1432-0428
DOI:	10.1007/s00125-016-4076-3