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Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.

Author:
  • Valeriya Lyssenko
  • Cecilia Nagorny
  • Michael R Erdos
  • Nils Wierup
  • Anna Jonsson
  • Peter Spégel
  • Marco Bugliani
  • Richa Saxena
  • Malin Fex
  • Nicolo Pulizzi
  • Bo Isomaa
  • Tiinamaija Tuomi
  • Peter Nilsson
  • Johanna Kuusisto
  • Jaakko Tuomilehto
  • Michael Boehnke
  • David Altshuler
  • Frank Sundler
  • Johan G Eriksson
  • Anne U Jackson
  • Markku Laakso
  • Piero Marchetti
  • Richard M Watanabe
  • Hindrik Mulder
  • Leif Groop
Publishing year: 2009
Language: English
Pages: 82-88
Publication/Series: Nature Genetics
Volume: 41
Issue: 1
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Diabetes and Endocrinology
  • Diabetes and Celiac Unit
  • Internal Medicine
  • ISSN: 1546-1718
Peter Spegel
E-mail: peter [dot] spegel [at] chem [dot] lu [dot] se

Researcher

Centre for Analysis and Synthesis

1

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00