title: Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function.
abstract: OBJECTIVE
  Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD(+) biosynthesis, exists as intracellular NAMPT (iNAMPT) and extracellular NAMPT (eNAMPT). eNAMPT, secreted from adipose tissue, promotes insulin secretion. Administration of nicotinamide mononucleotide (NMN), a product of the eNAMPT reaction, corrects impaired islet function in Nampt ( +/- ) mice. One of its potential targets is the NAD(+)-dependent deacetylase sirtuin 1. We hypothesised that altered NAMPT activity might contribute to the suppression of islet function associated with inflammation, and aimed to determine whether NMN could improve cytokine-mediated islet dysfunction.
  
  
  METHODS
  Acute effects of NMN on cytokine-mediated islet dysfunction were examined in islets incubated with TNFα and IL1β, and in mice fed a fructose-rich diet (FRD) for 16 weeks. Changes in iNAMPT, eNAMPT and inflammation levels were determined in FRD-fed mice.
  
  
  RESULTS
  FRD-fed mice displayed markedly lower levels of circulating eNAMPT, with impaired insulin secretion and raised islet expression of Il1b. NMN administration lowered Il1b expression and restored suppressed insulin secretion in FRD-fed mice. NMN also restored insulin secretion in islets cultured with pro-inflammatory cytokines. The changes in islet function corresponded with changes in key markers of islet function and differentiation. The anti-inflammatory effects of NMN were partially blocked by inhibition of sirtuin 1.
  
  
  CONCLUSIONS
  Chronic fructose feeding causes severe islet dysfunction in mice. Onset of beta cell failure in FRD-fed mice may occur via lowered secretion of eNAMPT, leading to increased islet inflammation and impaired beta cell function. Administration of exogenous NMN to FRD-fed mice corrects inflammation-induced islet dysfunction. Modulation of this pathway may be an attractive target for amelioration of islet dysfunction associated with inflammation.
authors: Centre for Diabetes, Blizard Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK. p.w.caton@qmul.ac.uk
authors: P W
authors: PW
authors: Caton
authors: J
authors: J
authors: Kieswich
authors: M M
authors: MM
authors: Yaqoob
authors: M J
authors: MJ
authors: Holness
authors: M C
authors: MC
authors: Sugden
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D005632:Fructose / Q000008:administration & dosage; D007249:Inflammation / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009537:Nicotinamide Mononucleotide / Q000008:administration & dosage* / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000097:blood / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
chemical_list: D016207:Cytokines; D007328:Insulin; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D009537:Nicotinamide Mononucleotide; D005632:Fructose; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D056564:Sirtuin 1