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Cited by 745Pancreatic function and diabetesCircadian rhythm and melatoninGenetic Associations and Epidemiology

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

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Lyssenko, Valeriya, Nagorny, Cecilia L F, Erdos, Michael R, Wierup, Nils, Jonsson, Anna, Spégel, Peter, Bugliani, Marco, Saxena, Richa +17 more·2009·Nature Genetics
DOI 10.1038/ng.288PMC PMC3725650
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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.

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  • The rs10830963 T2D risk variant is associated with impaired fasting glucose and measures of decreased insulin secretion in daytime OGTT assessments.

    “the rs10830963 T2D risk variant is associated with impaired fasting glucose and measures of decreased insulin secretion in daytime OGTT assessments (26).”

    From Interplay of Dinner Timing and <i>MTNR1B</i> Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [26]

    The results sections report that the rs10830963 risk G allele was associated with higher fasting glucose and lower measures of early insulin secretion; Methods identifies CIR and disposition index as OGTT-derived measures. The copy does not specify that the OGTTs were conducted during the daytime, and it reports higher fasting glucose rather than a categorical diagnosis of impaired fasting glucose. (LLM, conf=0.88)

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  • The genotype distribution in the ONTIME population mirrored that in a previous genome-wide association study of European ancestry, with G allele frequency 0.30 and genotype frequencies CC 50%, CG 40%, and GG 10%.

    “As expected, the genotype distribution in the ONTIME population mirrored that in previous genome-wide association study of European ancestry (G allele frequency 5 0.30 with CC, 50%; CG, 40%; and GG, 10%) (26).”

    From Interplay of Dinner Timing and <i>MTNR1B</i> Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial (2022) · cites this paper as [26]

    The section on future diabetes risk reports G-allele frequencies of 28.0%–31.0% in Swedish and Finnish cohorts, consistent with approximately 0.30. The Genotyping Methods say genotypes were in Hardy–Weinberg equilibrium, but our copy does not report the cited CC 50%, CG 40%, and GG 10% frequencies for a European-ancestry GWAS population. The comparison with ONTIME is the citing authors’ own observation. (LLM, conf=0.84)

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Authors
Lyssenko, V., Nagorny, C. L. F., Erdos, M. R., Wierup, N., Jonsson, A., Spégel, P., Bugliani, M., Saxena, R., Fex, M., Pulizzi, N., Isomaa, B., Tuomi, T., Nilsson, P., Kuusisto, J., Tuomilehto, J., Boehnke, M., Altshuler, D., Sundler, F., Eriksson, J. G., Jackson, A. U., Laakso, M., Marchetti, P., Watanabe, R. M., Mulder, H., & Groop, L.
Affiliations
  • Lund University (SE)
  • National Human Genome Research Institute (US)
  • University of Pisa (IT)
  • Broad Institute (US)
  • Folkhälsans Forskningscentrum (FI)
  • University of Helsinki (FI)
  • Kuopio University Hospital (FI)
  • University of Michigan (US)
  • University of Southern California (US)
Corresponding author
Groop, Leif
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2008-12-07
Volume
41
Issue
1
Pages
82-88
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.288
PMC
PMC3725650
OpenAlex
W2126776706
Cited by
742
References
31
Citations by year
2026: 21 · 2025: 22 · 2024: 32 · 2023: 28 · 2022: 25 · 2021: 40 · 2020: 33 · 2019: 35 · 2018: 46 · 2017: 50 · 2016: 46 · 2015: 51 · 2014: 48 · 2013: 42 · 2012: 51
FWCI
60.06
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders
  • National Institutes of Health
  • National Human Genome Research Institute (Z01HG000024)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072193, U01DK062370, R56DK062370, DK-062370, R01DK062370)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
MTNR1B, type 2 diabetes, insulin secretion, early insulin response, glucose tolerance, pancreatic beta cells, pancreatic islets, melatonin, genetic susceptibility, risk alleles, insulin release inhibition
MeSH terms
Insulin Secretion, Aged, Animals, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Humans, Insulin, Islets of Langerhans, Male, Middle Aged, Cohort Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Protein Transport, Receptors, Melatonin, Receptor, Melatonin, MT2, Mice, Rats

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