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

Lyssenko, Valeriya; Nagorny, Cecilia LU ; Erdos, Michael R; Wierup, Nils LU ; Jonsson, Anna LU ; Spégel, Peter LU ; Bugliani, Marco; Saxena, Richa; Fex, Malin LU and Pulizzi, Nicolo LU , et al. (2009) In Nature Genetics 41(1). p.82-88
Abstract
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... (More)
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. (Less)
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Contribution to journal
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published
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Nature Genetics
volume
41
issue
1
pages
82 - 88
publisher
Nature Publishing Group
external identifiers
  • WOS:000262085300020
  • PMID:19060908
  • Scopus:58149175669
ISSN
1546-1718
DOI
10.1038/ng.288
language
English
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yes
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14eac4a4-1876-400b-b454-15977c5178d3 (old id 1276379)
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http://www.ncbi.nlm.nih.gov/pubmed/19060908?dopt=Abstract
date added to LUP
2009-01-09 11:51:49
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2016-12-04 04:40:35
@misc{14eac4a4-1876-400b-b454-15977c5178d3,
  abstract     = {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.},
  author       = {Lyssenko, Valeriya and Nagorny, Cecilia and Erdos, Michael R and Wierup, Nils and Jonsson, Anna and Spégel, Peter and Bugliani, Marco and Saxena, Richa and Fex, Malin and Pulizzi, Nicolo and Isomaa, Bo and Tuomi, Tiinamaija and Nilsson, Peter and Kuusisto, Johanna and Tuomilehto, Jaakko and Boehnke, Michael and Altshuler, David and Sundler, Frank and Eriksson, Johan G and Jackson, Anne U and Laakso, Markku and Marchetti, Piero and Watanabe, Richard M and Mulder, Hindrik and Groop, Leif},
  issn         = {1546-1718},
  language     = {eng},
  number       = {1},
  pages        = {82--88},
  publisher    = {ARRAY(0xbba5780)},
  series       = {Nature Genetics},
  title        = {Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.},
  url          = {http://dx.doi.org/10.1038/ng.288},
  volume       = {41},
  year         = {2009},
}