Cellular and Molecular Life Sciences

, Volume 74, Issue 21, pp 3941–3954 | Cite as

Melatonin, mitochondria, and the metabolic syndrome

  • Daniel P. CardinaliEmail author
  • Daniel E. Vigo
Multi-author review


A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed.


Melatonin Metabolic syndrome Mitochondria Inflammation Diabetes Obesity Insulin signaling Aging 



Adenosine monophosphate kinase


Blood pressure


Cyclic adenosine monophosphate




Glycated hemoglobin


Insulin receptor substrate 1




Mammalian target of rapamycin


Metabolic syndrome


Mitochondrial permeability transition pore


Nicotinamide adenine dinucleotide+


Nitric oxide


Reactive nitrogen species


Reactive oxygen species


Single-nucleotide polymorphisms


Tumor necrosis factor



Studies in authors’ laboratory were supported by Grants PICT 2007 01045 and 2012 0984 from the Agencia Nacional de Promoción Científica y Tecnológica, Argentina.


  1. 1.
    Smith CJ, Ryckman KK (2015) Epigenetic and developmental influences on the risk of obesity, diabetes, and metabolic syndrome. Diabetes Metab Syndr Obes 8:295–302PubMedPubMedCentralGoogle Scholar
  2. 2.
    O’Neill S, O’Driscoll L (2015) Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 16:1–12PubMedCrossRefGoogle Scholar
  3. 3.
    Bhatti JS, Kumar S, Vijayan M, Bhatti GK, Reddy PH (2017) Therapeutic strategies for mitochondrial dysfunction and oxidative stress in age-related metabolic disorders. Prog Mol Biol Transl Sci 146:13–46PubMedCrossRefGoogle Scholar
  4. 4.
    Bhatti JS, Bhatti GK, Reddy PH (2016) Mitochondrial dysfunction and oxidative stress in metabolic disorders—a step towards mitochondria based therapeutic strategies. Biochim Biophys Acta. doi: 10.1016/j.bbadis.2016.11.010 (Epub ahead of print) PubMedGoogle Scholar
  5. 5.
    Fabbri E, Chia CW, Spencer RG, Fishbein KW, Reiter DA, Cameron D, Zane AC, Moore ZA, Gonzalez-Freire M, Zoli M, Studenski SA, Kalyani RR, Egan JM, Ferrucci L (2017) Insulin resistance is associated with reduced mitochondrial oxidative capacity measured by 31P-magnetic resonance spectroscopy in participants without diabetes from the Baltimore Longitudinal Study of Aging. Diabetes 66:170–176PubMedCrossRefGoogle Scholar
  6. 6.
    Di Daniele N, Noce A, Vidiri MF, Moriconi E, Marrone G, Annicchiarico-Petruzzelli M, D’Urso G, Tesauro M, Rovella V, De Lorenzo A (2017) Impact of Mediterranean diet on metabolic syndrome, cancer and longevity. Oncotarget. 8:8947–8979PubMedGoogle Scholar
  7. 7.
    de la Iglesia R, Loria-Kohen V, Zulet MA, Martinez JA, Reglero G, de Ramirez MA (2016) Dietary strategies implicated in the prevention and treatment of metabolic syndrome. Int J Mol, Sci, p 17Google Scholar
  8. 8.
    Kalsbeek A, la Fleur S, Fliers E (2014) Circadian control of glucose metabolism. Mol Metab 3:372–383PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Huang W, Ramsey KM, Marcheva B, Bass J (2011) Circadian rhythms, sleep, and metabolism. J Clin Invest 121:2133–2141PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Karthikeyan R, Marimuthu G, Spence DW, Pandi-Perumal SR, Bahammam AS, Brown GM, Cardinali DP (2014) Should we listen to our clock to prevent type 2 diabetes mellitus? Diabetes Res Clin Pract 106:182–190PubMedCrossRefGoogle Scholar
  11. 11.
    McFadden E, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ (2014) The relationship between obesity and exposure to light at night: cross-sectional analyses of over 100,000 women in the Breakthrough Generations Study. Am J Epidemiol 180:245–250PubMedCrossRefGoogle Scholar
  12. 12.
    Molzof HE, Wirth MD, Burch JB, Shivappa N, Hebert JR, Johnson RL, Gamble KL (2017) The impact of meal timing on cardiometabolic syndrome indicators in shift workers. Chronobiol Int 34:337–348PubMedCrossRefGoogle Scholar
  13. 13.
    Lin YC, Hsieh IC, Chen PC (2015) Utilizing the metabolic syndrome component count in workers’ health surveillance: an example of day-time vs. day-night rotating shift workers. Int J Occup Med Environ Health 28:675–688PubMedCrossRefGoogle Scholar
  14. 14.
    Kawabe Y, Nakamura Y, Kikuchi S, Murakami Y, Tanaka T, Takebayashi T, Okayama A, Miura K, Okamura T, Ueshima H (2014) Relationship between shift work and clustering of the metabolic syndrome diagnostic components. J Atheroscler Thromb 21:703–711PubMedCrossRefGoogle Scholar
  15. 15.
    Arora T, Chen MZ, Cooper AR, Andrews RC, Taheri S (2016) The impact of sleep debt on excess adiposity and insulin sensitivity in patients with early type 2 diabetes mellitus. J Clin Sleep Med 12:673–680PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Cardinali DP, Cano P, Jimenez-Ortega V, Esquifino AI (2011) Melatonin and the metabolic syndrome: physiopathologic and therapeutical implications. Neuroendocrinology 93:133–142PubMedCrossRefGoogle Scholar
  17. 17.
    Cardinali DP, Hardeland R (2017) Inflammaging, metabolic syndrome and melatonin: a call for treatment studies. Neuroendocrinology 104:382–397PubMedCrossRefGoogle Scholar
  18. 18.
    Tan DX, Manchester LC, Esteban-Zubero E, Zhou Z, Reiter RJ (2015) Melatonin as a potent and inducible endogenous antioxidant: synthesis and metabolism. Molecules 20:18886–18906PubMedCrossRefGoogle Scholar
  19. 19.
    Hardeland R, Cardinali DP, Brown GM, Pandi-Perumal SR (2015) Melatonin and brain inflammaging. Prog Neurobiol 127–128:46–63PubMedCrossRefGoogle Scholar
  20. 20.
    Sharafati-Chaleshtori R, Shirzad H, Rafieian-Kopaei M, Soltani A (2017) Melatonin and human mitochondrial diseases. J Res Med Sci 22:2PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Balistreri CR, Caruso C, Candore G (2010) The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediators Inflamm 2010:802078PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Makki K, Froguel P, Wolowczuk I (2013) Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm 2013:139239PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Welty FK, Alfaddagh A, Elajami TK (2016) Targeting inflammation in metabolic syndrome. Transl Res 167:257–280PubMedCrossRefGoogle Scholar
  24. 24.
    Esser N, Paquot N, Scheen AJ (2015) Inflammatory markers and cardiometabolic diseases. Acta Clin Belg 70:193–199PubMedCrossRefGoogle Scholar
  25. 25.
    Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM (2010) Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res 48:297–310PubMedCrossRefGoogle Scholar
  26. 26.
    Crino PB (2016) The mTOR signalling cascade: paving new roads to cure neurological disease. Nat Rev Neurol 12:379–392PubMedCrossRefGoogle Scholar
  27. 27.
    Zhao D, Yang J, Yang L (2017) Insights for oxidative stress and mTOR signaling in myocardial ischemia/reperfusion injury under diabetes. Oxid Med Cell Longev 2017:6437467PubMedPubMedCentralGoogle Scholar
  28. 28.
    Arpaci D, Gurkan TA, Yilmaz S, Ergenc H, Tamer A, Keser N, Gunduz H (2015) The relationship between epicardial fat tissue thickness and visceral adipose tissue in lean patients with polycystic ovary syndrome. J Ovarian Res 8:71PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Sarvari AK, Vereb Z, Uray IP, Fesus L, Balajthy Z (2014) Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro. Biochem Biophys Res Commun 450:1383–1389PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang Y, Zitsman JL, Hou J, Fennoy I, Guo K, Feinberg J, Leibel RL (2014) Fat cell size and adipokine expression in relation to gender, depot, and metabolic risk factors in morbidly obese adolescents. Obesity (Silver Spring) 22:691–697CrossRefGoogle Scholar
  31. 31.
    Tchernof A, Despres JP (2013) Pathophysiology of human visceral obesity: an update. Physiol Rev 93:359–404PubMedCrossRefGoogle Scholar
  32. 32.
    Pereira-Miranda E, Costa PR, Queiroz VA, Pereira-Santos M, Santana ML (2017) Overweight and obesity associated with higher depression prevalence in adults: a systematic review and meta-analysis. J Am Coll Nutr 36:223–233PubMedCrossRefGoogle Scholar
  33. 33.
    Franceschi C, Bonafe M, Valensin S, Olivieri F, De LM, Ottaviani E, De BG (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254PubMedCrossRefGoogle Scholar
  34. 34.
    Boren E, Gershwin ME (2004) Inflamm-aging: autoimmunity, and the immune-risk phenotype. Autoimmun Rev 3:401–406PubMedCrossRefGoogle Scholar
  35. 35.
    Cevenini E, Monti D, Franceschi C (2013) Inflamm-ageing. Curr Opin Clin Nutr Metab Care 16:14–20PubMedCrossRefGoogle Scholar
  36. 36.
    Catrysse L, van Loo G (2017) Inflammation and the metabolic syndrome: the tissue-specific functions of NF-kappaβ. Trends Cell Biol. doi: 10.1016/j.tcb.2017.01.006 (Epub ahead of print) PubMedGoogle Scholar
  37. 37.
    De la Fuente M, Miquel J (2009) An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des 15:3003–3026PubMedCrossRefGoogle Scholar
  38. 38.
    Hardeland R (2013) Melatonin and the theories of aging: a critical appraisal of melatonin’s role in antiaging mechanisms. J Pineal Res 55:325–356PubMedGoogle Scholar
  39. 39.
    Tan DX, Manchester LC, Qin L, Reiter RJ (2016) Melatonin: a mitochondrial targeting molecule involving mitochondrial protection and dynamics. Int J Mol, Sci, p 17Google Scholar
  40. 40.
    Cardinali DP, Pagano ES, Scacchi Bernasconi PA, Reynoso R, Scacchi P (2013) Melatonin and mitochondrial dysfunction in the central nervous system. Horm Behav 63:322–330PubMedCrossRefGoogle Scholar
  41. 41.
    Tan DX, Manchester LC, Liu X, Rosales-Corral SA, Acuña-Castroviejo D, Reiter RJ (2013) Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. J Pineal Res 54:127–138PubMedCrossRefGoogle Scholar
  42. 42.
    Reiter RJ, Paredes SD, Manchester LC, Tan DX (2009) Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol 44:175–200PubMedCrossRefGoogle Scholar
  43. 43.
    Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR (2011) Melatonin–a pleiotropic, orchestrating regulator molecule. Prog Neurobiol 93:350–384PubMedCrossRefGoogle Scholar
  44. 44.
    Petrosillo G, Fattoretti P, Matera M, Ruggiero FM, Bertoni-Freddari C, Paradies G (2008) Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection. Rejuvenation Res 11:935–943PubMedCrossRefGoogle Scholar
  45. 45.
    Guarente L (2008) Mitochondria–a nexus for aging, calorie restriction, and sirtuins? Cell 132:171–176PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Mayo JC, Sainz RM, Gonzalez MP, Cepas V, Tan DX, Reiter RJ (2017) Melatonin and sirtuins: A “not-so unexpected” relationship. J Pineal Res 62(2). doi: 10.1111/jpi.12391
  47. 47.
    Hardeland R (2017) Melatonin and the pathologies of weakened or dysregulated circadian oscillators. J Pineal Res. doi: 10.1111/jpi.12377 (Epub 2016 Nov 24) PubMedGoogle Scholar
  48. 48.
    She M, Hou H, Wang Z, Zhang C, Laudon M, Yin W (2014) Melatonin rescues 3T3-L1 adipocytes from FFA-induced insulin resistance by inhibiting phosphorylation of IRS-1 on Ser307. Biochimie 103:126–130PubMedCrossRefGoogle Scholar
  49. 49.
    Teodoro BG, Baraldi FG, Sampaio IH, Bomfim LH, Queiroz AL, Passos MA, Carneiro EM, Alberici LC, Gomis R, Amaral FG, Cipolla-Neto J, Araujo MB, Lima T, Uyemura SA, Silveira LR, Vieira E (2014) Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle. J Pineal Res 57:155–156PubMedCrossRefGoogle Scholar
  50. 50.
    Quan X, Wang J, Liang C, Zheng H, Zhang L (2015) Melatonin inhibits tunicamycin-induced endoplasmic reticulum stress and insulin resistance in skeletal muscle cells. Biochem Biophys Res Commun 463:1102–1107PubMedCrossRefGoogle Scholar
  51. 51.
    Du Y, Wei T (2014) Inputs and outputs of insulin receptor. Protein Cell 5:203–213PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    She M, Deng X, Guo Z, Laudon M, Hu Z, Liao D, Hu X, Luo Y, Shen Q, Su Z, Yin W (2009) NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats. Pharmacol Res 59:248–253PubMedCrossRefGoogle Scholar
  53. 53.
    Prunet-Marcassus B, Desbazeille M, Bros A, Louche K, Delagrange P, Renard P, Casteilla L, Penicaud L (2003) Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity. Endocrinology 144:5347–5352PubMedCrossRefGoogle Scholar
  54. 54.
    Puchalski SS, Green JN, Rasmussen DD (2003) Melatonin effect on rat body weight regulation in response to high-fat diet at middle age. Endocrine 21:163–167PubMedCrossRefGoogle Scholar
  55. 55.
    Sartori C, Dessen P, Mathieu C, Monney A, Bloch J, Nicod P, Scherrer U, Duplain H (2009) Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice. Endocrinology 150:5311–5317PubMedCrossRefGoogle Scholar
  56. 56.
    Ladizesky MG, Boggio V, Albornoz LE, Castrillon PO, Mautalen C, Cardinali DP (2003) Melatonin increases oestradiol-induced bone formation in ovariectomized rats. J Pineal Res 34:143–151PubMedCrossRefGoogle Scholar
  57. 57.
    Sanchez-Mateos S, Alonso-Gonzalez C, Gonzalez A, Martinez-Campa CM, Mediavilla MD, Cos S, Sanchez-Barcelo EJ (2007) Melatonin and estradiol effects on food intake, body weight, and leptin in ovariectomized rats. Maturitas 58:91–101PubMedCrossRefGoogle Scholar
  58. 58.
    Ciortea R, Costin N, Braicu I, Haragas D, Hudacsko A, Bondor C, Mihu D, Mihu CM (2011) Effect of melatonin on intra-abdominal fat in correlation with endometrial proliferation in ovariectomized rats. Anticancer Res 31:2637–2643PubMedGoogle Scholar
  59. 59.
    Raskind MA, Burke BL, Crites NJ, Tapp AM, Rasmussen DD (2007) Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats. Neuropsychopharmacology 32:284–288PubMedCrossRefGoogle Scholar
  60. 60.
    De Pedro N, Martinez-Alvarez RM, Delgado MJ (2008) Melatonin reduces body weight in goldfish (Carassius auratus): effects on metabolic resources and some feeding regulators. J Pineal Res 45:32–39PubMedCrossRefGoogle Scholar
  61. 61.
    Rios-Lugo MJ, Cano P, Jimenez-Ortega V, Fernandez-Mateos MP, Scacchi PA, Cardinali DP, Esquifino AI (2010) Melatonin effect on plasma adiponectin, leptin, insulin, glucose, triglycerides and cholesterol in normal and high fat-fed rats. J Pineal Res 49:342–348PubMedCrossRefGoogle Scholar
  62. 62.
    Cuesta S, Kireev R, Forman K, Garcia C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA (2010) Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8). Exp Gerontol 45:950–956PubMedCrossRefGoogle Scholar
  63. 63.
    Cuesta S, Kireev R, Garcia C, Rancan L, Vara E, Tresguerres JA (2013) Melatonin can improve insulin resistance and aging-induced pancreas alterations in senescence-accelerated prone male mice (SAMP8). Age (Dordr.) 35:659–671CrossRefGoogle Scholar
  64. 64.
    Nduhirabandi F, du Toit EF, Blackhurst D, Marais D, Lochner A (2011) Chronic melatonin consumption prevents obesity-related metabolic abnormalities and protects the heart against myocardial ischemia and reperfusion injury in a prediabetic model of diet-induced obesity. J Pineal Res 50:171–182PubMedGoogle Scholar
  65. 65.
    Agil A, Navarro-Alarcon M, Ruiz R, Abuhamadah S, El-Mir MY, Vazquez GF (2011) Beneficial effects of melatonin on obesity and lipid profile in young Zucker diabetic fatty rats. J Pineal Res 50:207–212PubMedGoogle Scholar
  66. 66.
    Kitagawa A, Ohta Y, Ohashi K (2012) Melatonin improves metabolic syndrome induced by high fructose intake in rats. J Pineal Res 52:403–413PubMedCrossRefGoogle Scholar
  67. 67.
    Cardinali DP, Bernasconi PA, Reynoso R, Toso CF, Scacchi P (2013) Melatonin may curtail the metabolic syndrome: studies on initial and fully established fructose-induced metabolic syndrome in rats. Int J Mol Sci 14:2502–2514PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Bernasconi PA, Cardoso NP, Reynoso R, Scacchi P, Cardinali DP (2013) Melatonin and diet-induced metabolic syndrome in rats: impact on the hypophysial-testicular axis. Horm Mol Biol Clin Investig 16:101–112PubMedGoogle Scholar
  69. 69.
    Demirtas CY, Pasaoglu OT, Bircan FS, Kantar S, Turkozkan N (2015) The investigation of melatonin effect on liver antioxidant and oxidant levels in fructose-mediated metabolic syndrome model. Eur Rev Med Pharmacol Sci 19:1915–1921PubMedGoogle Scholar
  70. 70.
    Ewida SF, Al-Sharaky DR (2016) Implication of renal aquaporin-3 in fructose-induced metabolic syndrome and melatonin protection. J Clin Diagn Res 10:CF06–CF11PubMedPubMedCentralGoogle Scholar
  71. 71.
    Huang L, Zhang C, Hou Y, Laudon M, She M, Yang S, Ding L, Wang H, Wang Z, He P, Yin W (2013) Blood pressure reducing effects of piromelatine and melatonin in spontaneously hypertensive rats. Eur Rev Med Pharmacol Sci 17:2449–2456PubMedGoogle Scholar
  72. 72.
    Vinogradova I, Anisimov V (2013) Melatonin prevents the development of the metabolic syndrome in male rats exposed to different light/dark regimens. Biogerontology 14:401–409PubMedCrossRefGoogle Scholar
  73. 73.
    Hatzis G, Ziakas P, Kavantzas N, Triantafyllou A, Sigalas P, Andreadou I, Ioannidis K, Chatzis S, Filis K, Papalampros A, Sigala F (2013) Melatonin attenuates high fat diet-induced fatty liver disease in rats. World J Hepatol 5:160–169PubMedPubMedCentralGoogle Scholar
  74. 74.
    Diez ER, Renna NF, Prado NJ, Lembo C, Ponce Zumino AZ, Vazquez-Prieto M, Miatello RM (2013) Melatonin, given at the time of reperfusion, prevents ventricular arrhythmias in isolated hearts from fructose-fed rats and spontaneously hypertensive rats. J Pineal Res 55:166–173PubMedCrossRefGoogle Scholar
  75. 75.
    Agil A, Reiter RJ, Jimenez-Aranda A, Iban-Arias R, Navarro-Alarcon M, Marchal JA, Adem A, Fernandez-Vazquez G (2013) Melatonin ameliorates low-grade inflammation and oxidative stress in young Zucker diabetic fatty rats. J Pineal Res 54:381–388PubMedCrossRefGoogle Scholar
  76. 76.
    Bibak B, Khalili M, Rajaei Z, Soukhtanloo M, Hadjzadeh MA, Hayatdavoudi P (2014) Effects of melatonin on biochemical factors and food and water consumption in diabetic rats. Adv Biomed Res 3:173PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Hidayat M, Maha Y, Wasim H (2015) Effect of melatonin on serum glucose and body weight in sotreptozotocin induced diabetes in albino rats. J Ayub Med Coll Abbottabad 27:274–276PubMedGoogle Scholar
  78. 78.
    Pai SA, Majumdar AS (2014) Protective effects of melatonin against metabolic and reproductive disturbances in polycystic ovary syndrome in rats. J Pharm Pharmacol 66:1710–1721PubMedCrossRefGoogle Scholar
  79. 79.
    Cano BP, Pagano ES, Jimenez-Ortega V, Fernandez-Mateos P, Esquifino AI, Cardinali DP (2014) Melatonin normalizes clinical and biochemical parameters of mild inflammation in diet-induced metabolic syndrome in rats. J Pineal Res 57:280–290CrossRefGoogle Scholar
  80. 80.
    Rios-Lugo MJ, Jimenez-Ortega V, Cano-Barquilla P, Mateos PF, Spinedi EJ, Cardinali DP, Esquifino AI (2015) Melatonin counteracts changes in hypothalamic gene expression of signals regulating feeding behavior in high-fat fed rats. Horm Mol Biol Clin Investig 21:175–183PubMedGoogle Scholar
  81. 81.
    Favero G, Stacchiotti A, Castrezzati S, Bonomini F, Albanese M, Rezzani R, Rodella LF (2015) Melatonin reduces obesity and restores adipokine patterns and metabolism in obese (ob/ob) mice. Nutr Res 35:891–900PubMedCrossRefGoogle Scholar
  82. 82.
    Winiarska K, Dzik JM, Labudda M, Focht D, Sierakowski B, Owczarek A, Komorowski L, Bielecki W (2016) Melatonin nephroprotective action in Zucker diabetic fatty rats involves its inhibitory effect on NADPH oxidase. J Pin Res 60:109–117CrossRefGoogle Scholar
  83. 83.
    Doddigarla Z, Ahmad J, Parwez I (2016) Effect of chromium picolinate and melatonin either in single or in a combination in high carbohydrate diet-fed male Wistar rats. BioFactors 42:106–114PubMedGoogle Scholar
  84. 84.
    Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A (2016) Melatonin and l-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol 8:199–204PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Gao L, Zhao YC, Liang Y, Lin XH, Tan YJ, Wu DD, Li XZ, Ye BZ, Kong FQ, Sheng JZ, Huang HF (2016) The impaired myocardial ischemic tolerance in adult offspring of diabetic pregnancy is restored by maternal melatonin treatment. J Pineal Res 61:340–352PubMedCrossRefGoogle Scholar
  86. 86.
    Thomas AP, Hoang J, Vongbunyong K, Nguyen A, Rakshit K, Matveyenko AV (2016) Administration of melatonin and metformin prevents deleterious effects of circadian disruption and obesity in male rats. Endocrinology 157:4720–4731PubMedCrossRefGoogle Scholar
  87. 87.
    Sun H, Wang X, Chen J, Song K, Gusdon AM, Li L, Bu L, Qu S (2016) Melatonin improves non-alcoholic fatty liver disease via MAPK-JNK/P38 signaling in high-fat-diet-induced obese mice. Lipids Health Dis 15:202PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sheen JM, Chen YC, Hsu MH, Tain YL, Huang YH, Tiao MM, Li SW, Huang LT (2016) Melatonin alleviates liver apoptosis in bile duct ligation young rats. Int J Mol, Sci, p 17Google Scholar
  89. 89.
    Xu P, Wang J, Hong F, Wang S, Jin X, Xue T, Jia L, Zhai Y (2017) Melatonin prevents obesity through modulation of gut microbiota in mice. J Pineal Res. doi: 10.1111/jpi.12399 (Epub 2017 Mar 10) Google Scholar
  90. 90.
    Carrillo-Vico A, Lardone PJ, Alvarez-Sanchez N, Rodriguez-Rodriguez A, Guerrero JM (2013) Melatonin: buffering the immune system. Int J Mol Sci 14:8638–8683PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kireev RA, Tresguerres AC, Garcia C, Ariznavarreta C, Vara E, Tresguerres JA (2008) Melatonin is able to prevent the liver of old castrated female rats from oxidative and pro-inflammatory damage. J Pineal Res 45:394–402PubMedCrossRefGoogle Scholar
  92. 92.
    Cuesta S, Kireev R, Garcia C, Forman K, Escames G, Vara E, Tresguerres JA (2011) Beneficial effect of melatonin treatment on inflammation, apoptosis and oxidative stress on pancreas of a senescence accelerated mice model. Mech Ageing Dev 132:573–582PubMedCrossRefGoogle Scholar
  93. 93.
    Forman K, Vara E, Garcia C, Kireev R, Cuesta S, Escames G, Tresguerres JA (2011) Effect of a combined treatment with growth hormone and melatonin in the cardiological aging on male SAMP8 mice. J Gerontol A Biol Sci Med Sci 66:823–834PubMedCrossRefGoogle Scholar
  94. 94.
    Muhlbauer E, Wolgast S, Finckh U, Peschke D, Peschke E (2004) Indication of circadian oscillations in the rat pancreas. FEBS Lett 564:91–96PubMedCrossRefGoogle Scholar
  95. 95.
    Hardeland R, Madrid JA, Tan DX, Reiter RJ (2012) Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. J Pineal Res 52:139–166PubMedCrossRefGoogle Scholar
  96. 96.
    Boivin DB, James FO, Wu A, Cho-Park PF, Xiong H, Sun ZS (2003) Circadian clock genes oscillate in human peripheral blood mononuclear cells. Blood 102:4143–4145PubMedCrossRefGoogle Scholar
  97. 97.
    Bollinger T, Leutz A, Leliavski A, Skrum L, Kovac J, Bonacina L, Benedict C, Lange T, Westermann J, Oster H, Solbach W (2011) Circadian clocks in mouse and human CD4+ T cells. PLoS One 6:e29801PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hardeland R (2015) Melatonin and circadian oscillators in aging–a dynamic approach to the multiply connected players. Interdiscip Top Gerontol 40:128–140PubMedCrossRefGoogle Scholar
  99. 99.
    Jung KH, Hong SW, Zheng HM, Lee HS, Lee H, Lee DH, Lee SY, Hong SS (2010) Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaβ in rats. J Pineal Res 48:239–250PubMedCrossRefGoogle Scholar
  100. 100.
    Hardeland R (2014) Melatonin, noncoding RNAs, messenger RNA stability and epigenetics–evidence, hints, gaps and perspectives. Int J Mol Sci 15:18221–18252PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Pan M, Song YL, Xu JM, Gan HZ (2006) Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats. J Pineal Res 41:79–84PubMedCrossRefGoogle Scholar
  102. 102.
    Stumpf I, Bazwinsky I, Peschke E (2009) Modulation of the cGMP signaling pathway by melatonin in pancreatic beta-cells. J Pineal Res 46:140–147PubMedCrossRefGoogle Scholar
  103. 103.
    Kanter M, Uysal H, Karaca T, Sagmanligil HO (2006) Depression of glucose levels and partial restoration of pancreatic beta-cell damage by melatonin in streptozotocin-induced diabetic rats. Arch Toxicol 80:362–369PubMedCrossRefGoogle Scholar
  104. 104.
    Nishida S, Sato R, Murai I, Nakagawa S (2003) Effect of pinealectomy on plasma levels of insulin and leptin and on hepatic lipids in type 2 diabetic rats. J Pineal Res 35:251–256PubMedCrossRefGoogle Scholar
  105. 105.
    Nishida S, Segawa T, Murai I, Nakagawa S (2002) Long-term melatonin administration reduces hyperinsulinemia and improves the altered fatty-acid compositions in type 2 diabetic rats via the restoration of Delta-5 desaturase activity. J Pineal Res 32:26–33PubMedCrossRefGoogle Scholar
  106. 106.
    Mazepa RC, Cuevas MJ, Collado PS, Gonzalez-Gallego J (2000) Melatonin increases muscle and liver glycogen content in nonexercised and exercised rats. Life Sci 66:153–160PubMedCrossRefGoogle Scholar
  107. 107.
    Shieh JM, Wu HT, Cheng KC, Cheng JT (2009) Melatonin ameliorates high fat diet-induced diabetes and stimulates glycogen synthesis via a PKCzeta-Akt-GSK3beta pathway in hepatic cells. J Pineal Res 47:339–344PubMedCrossRefGoogle Scholar
  108. 108.
    Bartness TJ, Demas GE, Song CK (2002) Seasonal changes in adiposity: the roles of the photoperiod, melatonin and other hormones, and sympathetic nervous system. Exp Biol Med (Maywood) 227:363–376CrossRefGoogle Scholar
  109. 109.
    Tan DX, Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ (2011) Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev 12:167–188PubMedCrossRefGoogle Scholar
  110. 110.
    Tutuncu NB, Batur MK, Yildirir A, Tutuncu T, Deger A, Koray Z, Erbas B, Kabakci G, Aksoyek S, Erbas T (2005) Melatonin levels decrease in type 2 diabetic patients with cardiac autonomic neuropathy. J Pineal Res 39:43–49PubMedCrossRefGoogle Scholar
  111. 111.
    Peschke E, Stumpf I, Bazwinsky I, Litvak L, Dralle H, Muhlbauer E (2007) Melatonin and type 2 diabetes—a possible link? J Pineal Res 42:350–358PubMedCrossRefGoogle Scholar
  112. 112.
    Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJ, Manning AK, Jackson AU, Aulchenko Y, Potter SC, Erdos MR, Sanna S, Hottenga JJ, Wheeler E, Kaakinen M, Lyssenko V, Chen WM, Ahmadi K, Beckmann JS, Bergman RN, Bochud M, Bonnycastle LL, Buchanan TA, Cao A, Cervino A, Coin L, Collins FS, Crisponi L, de Geus EJ, Dehghan A, Deloukas P, Doney AS, Elliott P, Freimer N, Gateva V, Herder C, Hofman A, Hughes TE, Hunt S, Illig T, Inouye M, Isomaa B, Johnson T, Kong A, Krestyaninova M, Kuusisto J, Laakso M, Lim N, Lindblad U, Lindgren CM, McCann OT, Mohlke KL, Morris AD, Naitza S, Orru M, Palmer CN, Pouta A, Randall J, Rathmann W, Saramies J, Scheet P, Scott LJ, Scuteri A, Sharp S, Sijbrands E, Smit JH, Song K, Steinthorsdottir V, Stringham HM, Tuomi T, Tuomilehto J, Uitterlinden AG, Voight BF, Waterworth D, Wichmann HE, Willemsen G, Witteman JC, Yuan X, Zhao JH, Zeggini E, Schlessinger D, Sandhu M, Boomsma DI, Uda M, Spector TD, Penninx BW, Altshuler D, Vollenweider P, Jarvelin MR, Lakatta E, Waeber G, Fox CS, Peltonen L, Groop LC, Mooser V, Cupples LA, Thorsteinsdottir U, Boehnke M, Barroso I, Van Duijn C, Dupuis J, Watanabe RM, Stefansson K, McCarthy MI, Wareham NJ, Meigs JB, Abecasis GR (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41:77–81PubMedCrossRefGoogle Scholar
  113. 113.
    Huber M, Treszl A, Reibis R, Teichmann C, Zergibel I, Bolbrinker J, Scholze J, Wegscheider K, Voller H, Kreutz R (2013) Genetics of melatonin receptor type 2 is associated with left ventricular function in hypertensive patients treated according to guidelines. Eur J Intern Med 24:650–655PubMedCrossRefGoogle Scholar
  114. 114.
    Zheng C, Dalla MC, Cobelli C, Groop L, Zhao H, Bale AE, Shaw M, Duran E, Pierpont B, Caprio S, Santoro N (2015) A common variant in the MTNR1b gene is associated with increased risk of impaired fasting glucose (IFG) in youth with obesity. Obesity (Silver Spring) 23:1022–1029CrossRefGoogle Scholar
  115. 115.
    Song X, Sun X, Ma G, Sun Y, Shi Y, Du Y, Chen ZJ (2015) Family association study between melatonin receptor gene polymorphisms and polycystic ovary syndrome in Han Chinese. Eur J Obstet Gynecol Reprod Biol 195:108–112PubMedCrossRefGoogle Scholar
  116. 116.
    O’Brien IA, Lewin IG, O’Hare JP, Arendt J, Corrall RJ (1986) Abnormal circadian rhythm of melatonin in diabetic autonomic neuropathy. Clin Endocrinol (Oxf) 24:359–364CrossRefGoogle Scholar
  117. 117.
    Hikichi T, Tateda N, Miura T (2011) Alteration of melatonin secretion in patients with type 2 diabetes and proliferative diabetic retinopathy. Clin Ophthalmol 5:655–660PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Mantele S, Otway DT, Middleton B, Bretschneider S, Wright J, Robertson MD, Skene DJ, Johnston JD (2012) Daily rhythms of plasma melatonin, but not plasma leptin or leptin mRNA, vary between lean, obese and type 2 diabetic men. PLoS One 7:e37123PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP (2013) Melatonin secretion and the incidence of type 2 diabetes. JAMA 309:1388–1396PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Reutrakul S, Siwasaranond N, Nimitphong H, Saetung S, Chirakalwasan N, Chailurkit LO, Srijaruskul K, Ongphiphadhanakul B, Thakkinstian A (2017) Associations between nocturnal urinary 6-sulfatoxymelatonin, obstructive sleep apnea severity and glycemic control in type 2 diabetes. Chronobiol Int 34:382–392PubMedCrossRefGoogle Scholar
  121. 121.
    Shimada M, Seki H, Samejima M, Hayase M, Shirai F (2016) Salivary melatonin levels and sleep-wake rhythms in pregnant women with hypertensive and glucose metabolic disorders: a prospective analysis. Biosci Trends 10:34–41PubMedCrossRefGoogle Scholar
  122. 122.
    Matuszek MA, Anton A, Thillainathan S, Armstrong NJ (2015) Increased insulin following an oral glucose load, genetic variation near the melatonin receptor MTNR1B, but no biochemical evidence of endothelial dysfunction in young asian men and women. PLoS ONE 10:e0133611PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Zhan Y, Li C, Gao Q, Chen J, Yu S, Liu SG (2015) Association between the rs4753426 polymorphism in MTNR1B with fasting plasma glucose level and pancreatic beta-cell function in gestational diabetes mellitus. Genet Mol Res 14:8778–8785PubMedCrossRefGoogle Scholar
  124. 124.
    Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Pawlik A (2017) MTNR1A and MTNR1B gene polymorphisms in women with gestational diabetes. Gynecol Endocrinol 33:395–398PubMedCrossRefGoogle Scholar
  125. 125.
    Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Magi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparso T, Doney A, Voight BF, Stringham HM, Li M, Kanoni S, Shrader P, Cavalcanti-Proenca C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, Ingelsson E, An P, O’Connell J, Luan J, Elliott A, McCarroll SA, Payne F, Roccasecca RM, Pattou F, Sethupathy P, Ardlie K, Ariyurek Y, Balkau B, Barter P, Beilby JP, Ben Shlomo Y, Benediktsson R, Bennett AJ, Bergmann S, Bochud M, Boerwinkle E, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Bottcher Y, Brunner E, Bumpstead SJ, Charpentier G, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Cornelis M, Crawford G, Crisponi L, Day IN, de Geus EJ, Delplanque J, Dina C, Erdos MR, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Fox CS, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Groves CJ, Grundy S, Gwilliam R, Gyllensten U, Hadjadj S, Hallmans G, Hammond N, Han X, Hartikainen AL, Hassanali N, Hayward C, Heath SC, Hercberg S, Herder C, Hicks AA, Hillman DR, Hingorani AD, Hofman A, Hui J, Hung J, Isomaa B, Johnson PR, Jorgensen T, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Lyssenko V, Mahley R, Mangino M, Manning AK, Martinez-Larrad MT, McAteer JB, McCulloch LJ, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Morken MA, Mukherjee S, Naitza S, Narisu N, Neville MJ, Oostra BA, Orru M, Pakyz R, Palmer CN, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rathmann W, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Roden M, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Scott LJ, Seedorf U, Sharp SJ, Shields B, Sigurethsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvanen AC, Tanaka T, Thorand B, Tichet J, Tonjes A, Tuomi T, Uitterlinden AG, van Dijk KW, van Hoek M, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Walters GB, Ward KL, Watkins H, Weedon MN, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zeggini E, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Hattersley AT, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Rios M, Morris AD, Lind L, Palmer LJ, Hu FB, Franks PW, Ebrahim S, Marmot M, Kao WH, Pankow JS, Sampson MJ, Kuusisto J, Laakso M, Hansen T, Pedersen O, Pramstaller PP (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105–116PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Liao S, Liu Y, Tan Y, Gan L, Mei J, Song W, Chi S, Dong X, Chen X, Deng S (2012) Association of genetic variants of melatonin receptor 1B with gestational plasma glucose level and risk of glucose intolerance in pregnant Chinese women. PLoS One 7:e40113PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Liu C, Wu Y, Li H, Qi Q, Langenberg C, Loos RJ, Lin X (2010) MTNR1B rs10830963 is associated with fasting plasma glucose, HbA1C and impaired beta-cell function in Chinese Hans from Shanghai. BMC Med Genet 11:59PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Sakotnik A, Liebmann PM, Stoschitzky K, Lercher P, Schauenstein K, Klein W, Eber B (1999) Decreased melatonin synthesis in patients with coronary artery disease. Eur Heart J 20:1314–1317PubMedCrossRefGoogle Scholar
  129. 129.
    Girotti L, Lago M, Ianovsky O, Carbajales J, Elizari MV, Brusco LI, Cardinali DP (2000) Low urinary 6-sulphatoxymelatonin levels in patients with coronary artery disease. J Pineal Res 29:138–142PubMedCrossRefGoogle Scholar
  130. 130.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia MJ, Sanchez J, Marrero F, de Armas-Trujillo D (2002) Decreased nocturnal melatonin levels during acute myocardial infarction. J Pineal Res 33:248–252PubMedCrossRefGoogle Scholar
  131. 131.
    Yaprak M, Altun A, Vardar A, Aktoz M, Ciftci S, Ozbay G (2003) Decreased nocturnal synthesis of melatonin in patients with coronary artery disease. Int J Cardiol 89:103–107PubMedCrossRefGoogle Scholar
  132. 132.
    Obayashi K, Saeki K, Iwamoto J, Okamoto N, Tomioka K, Nezu S, Ikada Y, Kurumatani N (2013) Nocturnal urinary melatonin excretion is associated with non-dipper pattern in elderly hypertensives. Hypertens Res 36:736–740PubMedCrossRefGoogle Scholar
  133. 133.
    Cavallo A, Daniels SR, Dolan LM, Bean JA, Khoury JC (2004) Blood pressure-lowering effect of melatonin in type 1 diabetes. J Pineal Res 36:262–266PubMedCrossRefGoogle Scholar
  134. 134.
    Cavallo A, Daniels SR, Dolan LM, Khoury JC, Bean JA (2004) Blood pressure response to melatonin in type 1 diabetes. Pediatr Diabetes 5:26–31PubMedCrossRefGoogle Scholar
  135. 135.
    Cagnacci A, Cannoletta M, Renzi A, Baldassari F, Arangino S, Volpe A (2005) Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens 18:1614–1618PubMedCrossRefGoogle Scholar
  136. 136.
    Scheer FA, Van Montfrans GA, Van Someren EJ, Mairuhu G, Buijs RM (2004) Daily night-time melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 43:192–197PubMedCrossRefGoogle Scholar
  137. 137.
    Grossman E, Laudon M, Yalcin R, Zengil H, Peleg E, Sharabi Y, Kamari Y, Shen-Orr Z, Zisapel N (2006) Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med 119:898–902PubMedCrossRefGoogle Scholar
  138. 138.
    Mozdzan M, Mozdzan M, Chalubinski M, Wojdan K, Broncel M (2014) The effect of melatonin on circadian blood pressure in patients with type 2 diabetes and essential hypertension. Arch Med Sci 10:669–675PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Gubin DG, Gubin GD, Gapon LI, Weinert D (2016) Daily melatonin administration attenuates age-dependent disturbances of cardiovascular rhythms. Curr Aging Sci 9:5–13PubMedCrossRefGoogle Scholar
  140. 140.
    Wirtz PH, Bartschi C, Spillmann M, Ehlert U, von Kanel R (2008) Effect of oral melatonin on the procoagulant response to acute psychosocial stress in healthy men: a randomized placebo-controlled study. J Pineal Res 44:358–365PubMedCrossRefGoogle Scholar
  141. 141.
    Del Zar MM, Martinuzzo M, Cardinali DP, Carreras LO, Vacas MI (1990) Diurnal variation in melatonin effect on adenosine triphosphate and serotonin release by human platelets. Acta Endocrinol (Copenh) 123:453–458Google Scholar
  142. 142.
    Del Zar MM, Martinuzzo M, Falcon C, Cardinali DP, Carreras LO, Vacas MI (1990) Inhibition of human platelet aggregation and thromboxane-B2 production by melatonin: evidence for a diurnal variation. J Clin Endocrinol Metab 70:246–251PubMedCrossRefGoogle Scholar
  143. 143.
    Vacas MI, Del Zar MM, Martinuzzo M, Falcon C, Carreras LO, Cardinali DP (1991) Inhibition of human platelet aggregation and thromboxane B2 production by melatonin. Correlation with plasma melatonin levels. J Pineal Res 11:135–139PubMedCrossRefGoogle Scholar
  144. 144.
    Kozirog M, Poliwczak AR, Duchnowicz P, Koter-Michalak M, Sikora J, Broncel M (2011) Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome. J Pineal Res 50:261–266PubMedCrossRefGoogle Scholar
  145. 145.
    Goyal A, Terry PD, Superak HM, Nell-Dybdahl CL, Chowdhury R, Phillips LS, Kutner MH (2014) Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial. Diabetol Metab Syndr 6:124PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Romo-Nava F, Alvarez-Icaza GD, Fresan-Orellana A, Saracco AR, Becerra-Palars C, Moreno J, Ontiveros Uribe MP, Berlanga C, Heinze G, Buijs RM (2014) Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord 16:410–421PubMedCrossRefGoogle Scholar
  147. 147.
    Modabbernia A, Heidari P, Soleimani R, Sobhani A, Roshan ZA, Taslimi S, Ashrafi M, Modabbernia MJ (2014) Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res 53:133–140PubMedCrossRefGoogle Scholar
  148. 148.
    Mostafavi A, Solhi M, Mohammadi MR, Hamedi M, Keshavarzi M, Akhondzadeh S (2014) Melatonin decreases olanzapine induced metabolic side-effects in adolescents with bipolar disorder: a randomized double-blind placebo-controlled trial. Acta Med Iran 52:734–739PubMedGoogle Scholar
  149. 149.
    Shatilo VB, Bondarenko EV, Antoniuk-Shcheglova IA (2010) Pineal gland melatonin-producing function in elderly patients with hypertensive disease: age peculiarities. Adv Gerontol 23:539–542PubMedGoogle Scholar
  150. 150.
    Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N (2011) Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab Syndr Obes 4:307–313PubMedPubMedCentralGoogle Scholar
  151. 151.
    Gonciarz M, Gonciarz Z, Bielanski W, Mularczyk A, Konturek PC, Brzozowski T, Konturek SJ (2012) The effects of long-term melatonin treatment on plasma liver enzymes levels and plasma concentrations of lipids and melatonin in patients with nonalcoholic steatohepatitis: a pilot study. J Physiol Pharmacol 63:35–40PubMedGoogle Scholar
  152. 152.
    Gonciarz M, Gonciarz Z, Bielanski W, Mularczyk A, Konturek PC, Brzozowski T, Konturek SJ (2010) 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 61:705–710PubMedGoogle Scholar
  153. 153.
    Hussain SA, Khadim HM, Khalaf BH, Ismail SH, Hussein KI, Sahib AS (2006) Effects of melatonin and zinc on glycemic control in type 2 diabetic patients poorly controlled with metformin. Saudi Med J 27:1483–1488PubMedGoogle Scholar
  154. 154.
    Mesri AN, Mahdavi R, Roshanravan N, Lotfi YN, Ostadrahimi AR, Faramarzi E (2015) A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Horm Metab Res 47:504–508Google Scholar
  155. 155.
    Rubio-Sastre P, Scheer FA, Gomez-Abellan P, Madrid JA, Garaulet M (2014) Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep 37:1715–1719PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Chojnacki C, Walecka-Kapica E, Klupinska G, Pawlowicz M, Blonska A, Chojnacki J (2015) Effects of fluoxetine and melatonin on mood, sleep quality and body mass index in postmenopausal women. J Physiol Pharmacol 66:665–671PubMedGoogle Scholar
  157. 157.
    Tuomi T, Nagorny CL, Singh P, Bennet H, Yu Q, Alenkvist I, Isomaa B, Ostman B, Soderstrom J, Pesonen AK, Martikainen S, Raikkonen K, Forsen T, Hakaste L, Almgren P, Storm P, Asplund O, Shcherbina L, Fex M, Fadista J, Tengholm A, Wierup N, Groop L, Mulder H (2016) Increased melatonin signaling is a risk factor for type 2 diabetes. Cell Metab 23:1067–1077PubMedCrossRefGoogle Scholar
  158. 158.
    Amstrup AK, Sikjaer T, Pedersen SB, Heickendorff L, Mosekilde L, Rejnmark L (2016) Reduced fat mass and increased lean mass in response to 1 year of melatonin treatment in postmenopausal women: a randomized placebo-controlled trial. Clin Endocrinol (Oxf) 84:342–347CrossRefGoogle Scholar
  159. 159.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, de la Torre-Hernandez JM, Gonzalez-Gonzalez J, Garcia-Camarero T, Consuegra-Sanchez L, Garcia-Saiz MD, Aldea-Perona A, Virgos-Aller T, Azpeitia A, Reiter RJ (2017) Effect of intravenous and intracoronary melatonin as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: Results of the Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty trial. J Pineal Res. doi: 10.1111/jpi.12374 PubMedGoogle Scholar
  160. 160.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, de la Torre-Hernandez JM, Gonzalez-Gonzalez J, Garcia-Camarero T, Consuegra-Sanchez L, Garcia-Saiz MD, Aldea-Perona A, Virgos-Aller T, Azpeitia A, Reiter RJ (2017) Usefulness of early treatment with melatonin to reduce infarct size in patients with ST-segment elevation myocardial infarction receiving percutaneous coronary intervention (from the Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty Trial). Am J Cardiol 120:522–526PubMedCrossRefGoogle Scholar
  161. 161.
    McMullan CJ, Rimm EB, Schernhammer ES, Forman JP (2017) A nested case-control study of the association between melatonin secretion and incident myocardial infarction. Heart 103:694–701PubMedCrossRefGoogle Scholar
  162. 162.
    Grossman E, Laudon M, Zisapel N (2011) Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials. Vasc Health Risk Manag 7:577–584PubMedPubMedCentralGoogle Scholar
  163. 163.
    Tamura H, Nakamura Y, Narimatsu A, Yamagata Y, Takasaki A, Reiter RJ, Sugino N (2008) Melatonin treatment in peri- and postmenopausal women elevates serum high-density lipoprotein cholesterol levels without influencing total cholesterol levels. J Pineal Res 45:101–105PubMedCrossRefGoogle Scholar
  164. 164.
    Hussain SA (2007) Effect of melatonin on cholesterol absorption in rats. J Pineal Res 42:267–271PubMedCrossRefGoogle Scholar
  165. 165.
    Esquifino A, Agrasal C, Velazquez E, Villanua MA, Cardinali DP (1997) Effect of melatonin on serum cholesterol and phospholipid levels, and on prolactin, thyroid-stimulating hormone and thyroid hormone levels, in hyperprolactinemic rats. Life Sci 61:1051–1058PubMedCrossRefGoogle Scholar
  166. 166.
    McMullan CJ, Curhan GC, Schernhammer ES, Forman JP (2013) Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women. Am J Epidemiol 178:231–238PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Eckel RH, Depner CM, Perreault L, Markwald RR, Smith MR, McHill AW, Higgins J, Melanson EL, Wright KP Jr (2015) Morning circadian misalignment during short sleep duration impacts insulin sensitivity. Curr Biol 25:3004–3010PubMedCrossRefGoogle Scholar
  168. 168.
    Staiger H, Machicao F, Schafer SA, Kirchhoff K, Kantartzis K, Guthoff M, Silbernagel G, Stefan N, Haring HU, Fritsche A (2008) Polymorphisms within the novel type 2 diabetes risk locus MTNR1B determine beta-cell function. PLoS One 3:e3962PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spegel 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 JG, Jackson AU, Laakso M, Marchetti P, Watanabe RM, Mulder H, Groop L (2009) Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 41:82–88PubMedCrossRefGoogle Scholar
  170. 170.
    Langenberg C, Pascoe L, Mari A, Tura A, Laakso M, Frayling TM, Barroso I, Loos RJ, Wareham NJ, Walker M (2009) Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response. Diabetologia 52:1537–1542PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Marchetti P, Syed F, Suleiman M, Bugliani M, Marselli L (2012) From genotype to human beta cell phenotype and beyond. Islets 4:323–332PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Garaulet M, Gomez-Abellan P, Rubio-Sastre P, Madrid JA, Saxena R, Scheer FA (2015) Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans. Metabolism 64:1650–1657PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Barker A, Sharp SJ, Timpson NJ, Bouatia-Naji N, Warrington NM, Kanoni S, Beilin LJ, Brage S, Deloukas P, Evans DM, Grontved A, Hassanali N, Lawlor DA, Lecoeur C, Loos RJ, Lye SJ, McCarthy MI, Mori TA, Ndiaye NC, Newnham JP, Ntalla I, Pennell CE, St PB, Prokopenko I, Ring SM, Sattar N, Visvikis-Siest S, Dedoussis GV, Palmer LJ, Froguel P, Smith GD, Ekelund U, Wareham NJ, Langenberg C (2011) Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children. Diabetes 60:1805–1812PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Espino J, Pariente JA, Rodriguez AB (2011) Role of melatonin on diabetes-related metabolic disorders. World J Diabetes 2:82–91PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Bonnefond A, Clement N, Fawcett K, Yengo L, Vaillant E, Guillaume JL, Dechaume A, Payne F, Roussel R, Czernichow S, Hercberg S, Hadjadj S, Balkau B, Marre M, Lantieri O, Langenberg C, Bouatia-Naji N, Charpentier G, Vaxillaire M, Rocheleau G, Wareham NJ, Sladek R, McCarthy MI, Dina C, Barroso I, Jockers R, Froguel P (2012) Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet 44:297–301PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Karamitri A, Renault N, Clement N, Guillaume JL, Jockers R (2013) Minireview: toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes. Mol Endocrinol 27:1217–1233PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Lew KN, Wick A (2015) Pharmacotherapy of type 2 diabetes mellitus: navigating current and new therapies. Medsurg Nurs 24(413–9):438Google Scholar
  178. 178.
    Nauck MA, Friedrich N (2013) Do GLP-1-based therapies increase cancer risk? Diabetes Care 36(Suppl 2):S245–S252PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Weishaupt JH, Bartels C, Polking E, Dietrich J, Rohde G, Poeggeler B, Mertens N, Sperling S, Bohn M, Huther G, Schneider A, Bach A, Siren AL, Hardeland R, Bahr M, Nave KA, Ehrenreich H (2006) Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res 41:313–323PubMedCrossRefGoogle Scholar
  180. 180.
    Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (2012) Melatonin and its analogs in insomnia and depression. J Pineal Res 52:365–375PubMedCrossRefGoogle Scholar
  181. 181.
    Oxenkrug GF, Summergrad P (2010) Ramelteon attenuates age-associated hypertension and weight gain in spontaneously hypertensive rats. Ann N Y Acad Sci 1199:114–120PubMedCrossRefGoogle Scholar
  182. 182.
    She M, Hu X, Su Z, Zhang C, Yang S, Ding L, Laudon M, Yin W (2014) Piromelatine, a novel melatonin receptor agonist, stabilizes metabolic profiles and ameliorates insulin resistance in chronic sleep restricted rats. Eur J Pharmacol 727:60–65PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.BIOMED-UCA-CONICET and Department of Teaching and Research, Faculty of Medical SciencesPontificia Universidad Católica ArgentinaBuenos AiresArgentina

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