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Tired of Diabetes Genetics? Circadian Rhythms and Diabetes: The MTNR1B Story?

  • Genetics (T Frayling, Section Editor)
  • Published:
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Abstract

Circadian rhythms are ubiquitous in biological systems and regulate metabolic processes throughout the body. Misalliance of these circadian rhythms and the systems they regulate has a profound impact on hormone levels and increases risk of developing metabolic diseases. Melatonin, a hormone secreted by the pineal gland, is one of the major signaling molecules used by the master circadian oscillator to entrain downstream circadian rhythms. Several recent genetic studies have pointed out that a common variant in the gene that encodes the melatonin receptor 2 (MTNR1B) is associated with impaired glucose homeostasis, reduced insulin secretion, and an increased risk of developing type 2 diabetes. Here, we try to review the role of this receptor and its signaling pathways in respect to glucose homeostasis and development of the disease.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Green CB, Takahashi JS, Bass J. The meter of metabolism. Cell. 2008;134(5):728–42.

    Article  PubMed  CAS  Google Scholar 

  2. Lamia KA, Evans RM. Metabolism: tick, tock, a beta-cell clock. Nature. 2010;466(7306):571–2.

    Article  PubMed  CAS  Google Scholar 

  3. Stamenkovic JA, Olsson AH, Nagorny CL, Malmgren S, Dekker-Nitert M, Ling C, et al. Regulation of core clock genes in human islets. Metabolism. 2012;61(7):978–85.

    Article  PubMed  CAS  Google Scholar 

  4. Hardeland R, Madrid JA, Tan DX, Reiter RJ. Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. J Pineal Res. 2012;52(2):139–66.

    Article  PubMed  CAS  Google Scholar 

  5. Shea SA. Obesity and pharmacologic control of the body clock. N Eng J Med. 2012;367(2):175–8.

    Article  CAS  Google Scholar 

  6. Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106(11):4453–8.

    Article  PubMed  CAS  Google Scholar 

  7. Simonneaux V, Ribelayga C. Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Pharmacol Rev. 2003;55(2):325–95.

    Article  PubMed  CAS  Google Scholar 

  8. Boutin JA, Audinot V, Ferry G, Delagrange P. Molecular tools to study melatonin pathways and actions. Trends Pharmacol Sci. 2005;26(8):412–9.

    Article  PubMed  CAS  Google Scholar 

  9. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine. 2005;27(2):119–30.

    Article  PubMed  CAS  Google Scholar 

  10. Kvetnoy I, Sandvik AK, Waldum HL. The diffuse neuroendocrine system and extrapineal melatonin. J Mol Endocrinol. 1997;18(1):1–3.

    Article  PubMed  CAS  Google Scholar 

  11. Peschke E. Melatonin, endocrine pancreas and diabetes. J Pineal Res. 2008;44(1):26–40.

    PubMed  CAS  Google Scholar 

  12. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005;27(2):101–10.

    Article  PubMed  CAS  Google Scholar 

  13. Arendt J. Melatonin and the mammalian pineal gland. London: Chapman and Hall; 1994.

    Google Scholar 

  14. Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R. Melatonin: nature’s most versatile biological signal? FEBS J. 2006;273(13):2813–38.

    Article  PubMed  CAS  Google Scholar 

  15. Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S. Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms. 1997;12(6):604–17.

    Article  PubMed  CAS  Google Scholar 

  16. Arendt J. Does melatonin improve sleep? Efficacy of melatonin. BMJ. 2006;332(7540):550.

    Article  PubMed  Google Scholar 

  17. Zhdanova IV, Wurtman RJ. Efficacy of melatonin as a sleep-promoting agent. J Biol Rhythms. 1997;12(6):644–50.

    Article  PubMed  CAS  Google Scholar 

  18. Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, Dubocovich ML, et al. MT(2) melatonin receptors are present and functional in rat caudal artery. J Pharmacol Exp Ther. 2002;302(3):1295–302.

    Article  PubMed  CAS  Google Scholar 

  19. Weitzman ED, Fukushima D, Nogeire C, Roffwarg H, Gallagher TF, Hellman L. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. J Clin Endocrinol Metab. 1971;33(1):14–22.

    Article  PubMed  CAS  Google Scholar 

  20. Brydon L, Petit L, Delagrange P, Strosberg AD, Jockers R. Functional expression of MT2 (Mel1b) melatonin receptors in human PAZ6 adipocytes. Endocrinology. 2001;142(10):4264–71.

    Article  PubMed  CAS  Google Scholar 

  21. Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, et al. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res. 2006;41(1):67–72.

    Article  PubMed  CAS  Google Scholar 

  22. Poon AM, Choy EH, Pang SF. Modulation of blood glucose by melatonin: a direct action on melatonin receptors in mouse hepatocytes. Biol Signals Recept. 2001;10(6):367–79.

    Article  PubMed  CAS  Google Scholar 

  23. Peschke E, Frese T, Chankiewitz E, Peschke D, Preiss U, Schneyer U, et al. Diabetic Goto Kakizaki rats as well as type 2 diabetic patients show a decreased diurnal serum melatonin level and an increased pancreatic melatonin-receptor status. J Pineal Res. 2006;40(2):135–43.

    Article  PubMed  CAS  Google Scholar 

  24. Bailey CJ, Atkins TW, Matty AJ. Melatonin inhibition of insulin secretion in the rat and mouse. Horm Res. 1974;5(1):21–8.

    Article  PubMed  CAS  Google Scholar 

  25. Ramracheya RD, Muller DS, Squires PE, Brereton H, Sugden D, Huang GC, et al. Function and expression of melatonin receptors on human pancreatic islets. J Pineal Res. 2008;44(3):273–9.

    Article  PubMed  CAS  Google Scholar 

  26. Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol: WJG. 2011;17(34):3888–98.

    Article  PubMed  CAS  Google Scholar 

  27. Kemp DM, Ubeda M, Habener JF. Identification and functional characterization of melatonin Mel 1a receptors in pancreatic beta cells: potential role in incretin-mediated cell function by sensitization of cAMP signaling. Mol Cell Endocrinol. 2002;191(2):157–66.

    Article  PubMed  CAS  Google Scholar 

  28. von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res. 2002;309(1):151–62.

    Article  Google Scholar 

  29. Mazzucchelli C, Pannacci M, Nonno R, Lucini V, Fraschini F, Stankov BM. The melatonin receptor in the human brain: cloning experiments and distribution studies. Brain Res Mol Brain Res. 1996;39(1–2):117–26.

    Article  PubMed  CAS  Google Scholar 

  30. Al-Ghoul WM, Herman MD, Dubocovich ML. Melatonin receptor subtype expression in human cerebellum. Neuroreport. 1998;9(18):4063–8.

    Article  PubMed  CAS  Google Scholar 

  31. Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron. 1994;13(5):1177–85.

    Article  PubMed  CAS  Google Scholar 

  32. Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85(3):335–53.

    Article  PubMed  CAS  Google Scholar 

  33. Poirel VJ, Cailotto C, Streicher D, Pevet P, Masson-Pevet M, Gauer F. MT1 melatonin receptor mRNA tissular localization by PCR amplification. Neuro Endocrinol Lett. 2003;24(1–2):33–8.

    PubMed  CAS  Google Scholar 

  34. • Nagorny CL, Sathanoori R, Voss U, Mulder H, Wierup N. Distribution of melatonin receptors in murine pancreatic islets. J Pineal Res. 2011;50(4):412–7. This study provides evidence for the localization of melatonin receptors in mouse islets on the protein level, not only their expression, but also their cellular localization in the islet. It demonstrates that MT1 is expressed in α-cells while MT2 is located to the β-cells. These findings help to understand the complex machinery underlying melatonin’s role in the regulation of islet function.

    Article  PubMed  CAS  Google Scholar 

  35. Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A. 1995;92(19):8734–8.

    Article  PubMed  CAS  Google Scholar 

  36. Jockers R, Maurice P, Boutin JA, Delagrange P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what’s new? Br J Pharmacol. 2008;154(6):1182–95.

    Article  PubMed  CAS  Google Scholar 

  37. Muhlbauer E, Gross E, Labucay K, Wolgast S, Peschke E. Loss of melatonin signalling and its impact on circadian rhythms in mouse organs regulating blood glucose. Eur J Pharmacol. 2009;606(1–3):61–71.

    Article  PubMed  Google Scholar 

  38. Peschke E, Muhlbauer E, Musshoff U, Csernus VJ, Chankiewitz E, Peschke D. Receptor (MT(1)) mediated influence of melatonin on cAMP concentration and insulin secretion of rat insulinoma cells INS-1. J Pineal Res. 2002;33(2):63–71.

    Article  PubMed  CAS  Google Scholar 

  39. Peschke E, Bach AG, Muhlbauer E. Parallel signaling pathways of melatonin in the pancreatic beta-cell. J Pineal Res. 2006;40(2):184–91.

    Article  PubMed  CAS  Google Scholar 

  40. Masana MI, Dubocovich ML. Melatonin receptor signaling: finding the path through the dark. Sci Stke. 2001;2001(107):39.

    Article  Google Scholar 

  41. Stumpf I, Muhlbauer E, Peschke E. Involvement of the cGMP pathway in mediating the insulin-inhibitory effect of melatonin in pancreatic beta-cells. J Pineal Res. 2008;45(3):318–27.

    Article  PubMed  CAS  Google Scholar 

  42. Stumpf I, Bazwinsky I, Peschke E. Modulation of the cGMP signaling pathway by melatonin in pancreatic beta-cells. J Pineal Res. 2009;46(2):140–7.

    Article  PubMed  CAS  Google Scholar 

  43. •• Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spegel P, et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet. 2009;41(1):82–8. This study provides a comprehansive description of in vitro and in vivo effects of originally discovered common variant SNP rs10830963 in the MTNR1B gene on islet function and risk of type 2 diabetes.

    Article  PubMed  CAS  Google Scholar 

  44. • Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C, Sparso T, Holmkvist J, Marchand M, et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet. 2009;41(1):89–94. This is the first meta-analysis of genome-wide association studies for glucose and insulin levels. Together with another accompanying study (45) it identifies common variants in the MTNR1B gene to be associated with elevated glucose levels.

    Article  PubMed  CAS  Google Scholar 

  45. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet. 2009;41(1):77–81.

    Article  PubMed  CAS  Google Scholar 

  46. Gonciarz M, Gonciarz Z, Bielanski W, Mularczyk A, Konturek PC, Brzozowski T, et al. The pilot study of 3-month course of melatonin treatment of patients with nonalcoholic steatohepatitis: effect on plasma levels of liver enzymes, lipids and melatonin. J Physiol Pharmacol: Off J Polish Physiol Soc. 2010;61(6):705–10.

    CAS  Google Scholar 

  47. Walford GA, Green T, Neale B, Isakova T, Rotter JI, Grant SF, et al. Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism. Diabetologia. 2012;55(2):331–9.

    Article  PubMed  CAS  Google Scholar 

  48. Barker A, Sharp SJ, Timpson NJ, Bouatia-Naji N, Warrington NM, Kanoni S, et al. Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6000 children. Diabetes. 2011;60(6):1805–12.

    Article  PubMed  CAS  Google Scholar 

  49. •• Bonnefond A, Clement N, Fawcett K, Yengo L, Vaillant E, Guillaume JL, et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet. 2012;44(3):297–301. This is a first large scale exon re-sequencing study of the MTNR1B gene. It provides the first evidence on a number of rare variants in the MTNR1B gene with partial- or total-loss-of-function properties.

    Article  PubMed  CAS  Google Scholar 

  50. Kwak SH, Kim SH, Cho YM, Go MJ, Cho YS, Choi SH, et al. A genome-wide association study of gestational diabetes mellitus in Korean women. Diabetes. 2012;61(2):531–41.

    Article  PubMed  CAS  Google Scholar 

  51. Vlassi M, Gazouli M, Paltoglou G, Christopoulos P, Florentin L, Kassi G, et al. The rs10830963 variant of melatonin receptor MTNR1B is associated with increased risk for gestational diabetes mellitus in a Greek population. Hormones (Athens). 2012;11(1):70–6.

    Google Scholar 

  52. Liao S, Liu Y, Tan Y, Gan L, Mei J, Song W, et al. Association of genetic variants of melatonin receptor 1B with gestational plasma glucose level and risk of glucose intolerance in pregnant Chinese women. PLoS One. 2012;7(7):e40113.

    Article  PubMed  CAS  Google Scholar 

  53. Wang Y, Nie M, Li W, Ping F, Hu Y, Ma L, et al. Association of six single nucleotide polymorphisms with gestational diabetes mellitus in a Chinese population. PLoS One. 2011;6(11):e26953.

    Article  PubMed  CAS  Google Scholar 

  54. Dietrich K, Birkmeier S, Schleinitz D, Breitfeld J, Enigk B, Muller I, et al. Association and evolutionary studies of the melatonin receptor 1B gene (MTNR1B) in the self-contained population of Sorbs from Germany. Diab Med: J Br Diabet Assoc. 2011;28(11):1373–80.

    Article  CAS  Google Scholar 

  55. Muhlbauer E, Albrecht E, Hofmann K, Bazwinsky-Wutschke I, Peschke E. Melatonin inhibits insulin secretion in rat insulinoma beta-cells (INS-1) heterologously expressing the human melatonin receptor isoform MT2. J Pineal Res. 2011;51(3):361–72.

    Article  PubMed  Google Scholar 

  56. Sparso T, Bonnefond A, Andersson E, Bouatia-Naji N, Holmkvist J, Wegner L, et al. G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605. Diabetes. 2009;58(6):1450–6.

    Article  Google Scholar 

  57. Vangipurapu J, Stancakova A, Pihlajamaki J, Kuulasmaa TM, Kuulasmaa T, Paananen J, et al. Association of indices of liver and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 diabetes in 6,733 non-diabetic Finnish men. Diabetologia. 2011;54(3):563–71.

    Article  PubMed  CAS  Google Scholar 

  58. Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N. Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab Syndr Obes: Targets Ther. 2011;4:307–13.

    CAS  Google Scholar 

  59. Peschke E, Hofmann K, Ponicke K, Wedekind D, Muhlbauer E. Catecholamines are the key for explaining the biological relevance of insulin-melatonin antagonisms in type 1 and type 2 diabetes. J Pineal Res. 2012;52(4):389–96.

    Article  PubMed  CAS  Google Scholar 

  60. Illig T, Gieger C, Zhai G, Romisch-Margl W, Wang-Sattler R, Prehn C, et al. A genome-wide perspective of genetic variation in human metabolism. Nat Genet. 2010;42(2):137–41.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

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

    Cecilia Nagorny

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

    Valeriya Lyssenko

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  1. Cecilia Nagorny
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Correspondence to Cecilia Nagorny.

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Nagorny, C., Lyssenko, V. Tired of Diabetes Genetics? Circadian Rhythms and Diabetes: The MTNR1B Story?. Curr Diab Rep 12, 667–672 (2012). https://doi.org/10.1007/s11892-012-0327-y

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