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

Nature Genetics volume 41, pages 82–88 (2009)Cite this article

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 β 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 β 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 β cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.

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Figure 1: Insulin secretion according to different MTNR1B rs10830963 genotypes.
Figure 2: Colocalization of MTNR1B and insulin protein in mouse, rat and human pancreatic islets.
Figure 3: Expression of MTNR1B in human pancreatic islets.

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Acknowledgements

The DGI study was supported by a grant from Novartis.

Studies in Malmoe were supported by grants from the Swedish Research Council, including a Linné grant (No. 31475113580), the Diabetes Programme at Lund University, the Påhlsson Foundation, the Heart and Lung Foundation, the Wallenberg Foundation, the Swedish Diabetes Research Society, the Crafoord Foundation, Swedish Medical Society, Swedish Royal Physiographic Society, a Nordic Centre of Excellence Grant in Disease Genetics, the Finnish Diabetes Research Society, the Sigrid Juselius Foundation, Folkhälsan Research Foundation, Novo Nordisk Foundation, the European Network of Genomic and Genetic Epidemiology (ENGAGE), the Wallenberg Foundation, the European Foundation for the Study of Diabetes (EFSD) and the Human Tissue facility at the Lund University Diabetes Center. Studies in human islets were supported in part by the Italian Ministry of University and Research (PRIN 2007-2008) and the European Community (LSHM-CT-2006-518153).

Pancreatic islets at US National Institutes of Health were obtained through the ICR Basic Science Islet Distribution Program (City of Hope Hospital, Joslin Diabetes Center, Northwestern University, Southern California Islet Consortium, University of Alabama Birmingham, University of Illinois, University of Miami, University of Minnesota, University of Pennsylvania, University of Wisconsin and Washington University), the Juvenile Diabetes Research Foundation Islet Resources (Washington University) and the National Disease Resource Interchange (NDRI).

The FUSION study would like to thank the many research volunteers who generously participated in the various studies represented in FUSION. We also thank A.J. Swift, M. Morken, P.S. Chines and N. Narisu for genotying and informatics support. Support for FUSION was provided by the following: NIH grant DK062370 (M. Boehnke), American Diabetes Association research grant 1-05-RA-140 (R.M.W.), DK072193 (K.L. Mohlke) and National Human Genome Research Institute intramural project number 1 Z01 HG000024 (F.S. Collins). The METSIM study was supported by Academy of Finland grant 124243 (M.L.).

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Authors and Affiliations

  1. Department of Clinical Sciences in Malmoe, Unit of Diabetes and Endocrinology, Lund University Diabetes Centre, University Hospital, Malmoe, 20520, Sweden

    Valeriya Lyssenko, Anna Jonsson & Leif Groop

  2. Department of Clinical Sciences in Malmoe, Unit of Molecular Metabolism, Lund University Diabetes Centre, Malmoe, 20502, Sweden

    Cecilia L F Nagorny, Peter Spégel & Hindrik Mulder

  3. Genome Technology Branch, National Human Genome Research Institute, Bethesda, 20892, Maryland, USA

    Michael R Erdos

  4. Department of Experimental Medical Science, Unit of Neuroendocrine Cell Biology, Lund University, Lund, 22184, Sweden

    Nils Wierup & Frank Sundler

  5. Department of Endocrinology and Metabolism, University of Pisa, Pisa, 56124, Italy

    Marco Bugliani, Nicolo Pulizzi & Piero Marchetti

  6. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA

    Richa Saxena & David Altshuler

  7. Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Richa Saxena & David Altshuler

  8. Department of Clinical Sciences in Malmoe, Unit for Diabetes and Celiac Disease, Lund University Diabetes Centre, Malmoe, 20502, Sweden

    Malin Fex

  9. Folkhalsan Research Centre, Helsinki, 00251, Finland

    Bo Isomaa & Tiinamaija Tuomi

  10. Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki, Helsinki, 00140, Finland

    Tiinamaija Tuomi & Leif Groop

  11. Department of Clinical Sciences, Medicine, Lund University, Malmoe, 20502, Sweden

    Peter Nilsson

  12. Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, 70210, Finland

    Johanna Kuusisto & Markku Laakso

  13. Department of Health Promotion and Chronic Disease Prevention, Diabetes Unit, National Public Health Institute, Helsinki, 00300, Finland

    Jaakko Tuomilehto

  14. Department of Public Health, University of Helsinki, Helsinki, 00014, Finland

    Jaakko Tuomilehto

  15. South Ostrobothnia Central Hospital, Senäjoki, 60220, Finland

    Jaakko Tuomilehto

  16. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Michael Boehnke & Anne U Jackson

  17. National Public Health Institute, Helsinki, 00300, Finland

    Johan G Eriksson

  18. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, 00014, Finland

    Johan G Eriksson

  19. Department of Preventive Medicine, University of Southern California, Los Angeles, 90033, California, USA

    Richard M Watanabe

  20. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, 90033, California, USA

    Richard M Watanabe

Authors
  1. Valeriya Lyssenko
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Contributions

V.L.: DGI GWAS, data analysis and draft of the report. C.L.F.N., M.R.E.: in vitro expression experiments and analysis, and draft of the report. N.W.: immunocytochemistry. A.J.: genotyping and data analysis. P.S.: in vitro expression experiments. M. Bugliani: microarray and human islets experiments. R.S.: DGI GWAS analysis. M.F.: in vitro physiology. N.P.: genotyping. B.I., T.T.: phenotyping in the Botnia study. P.N.: phenotyping in the Malmoe study. J.K.: data analysis in METSIM study. J.T.: phenotyping in the FUSION study. M. Boehnke: PI of the FUSION study. D.A.: PI of the DGI study. F.S.: immunocytochemistry. J.G.E.: phenotyping in the Helsinki Birth Cohort Study. A.U.J.: FUSION GWAS and data analysis. M.L.: PI of the METSIM study. P.M.: microarray and human islets experiments. R.M.W.: FUSION GWAS analysis. H.M.: design and supervision of in vitro study experiments and draft of the report. L.G. designed and supervised all parts of the study and drafted the report. All researchers took part in the revision of the report and approved the final version.

Corresponding author

Correspondence to Leif Groop.

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Lyssenko, V., Nagorny, C., Erdos, M. et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 41, 82–88 (2009). https://doi.org/10.1038/ng.288

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