Lower nocturnal urinary 6-sulfatoxymelatonin is associated with more severe insulin resistance in patients with prediabetes

Sirimon Reutrakul, Rungtip Sumritsopak, Sunee Saetung, Suwannee Chanprasertyothin, La-Or Chailurkit, Thunyarat Anothaisintawee, Sirimon Reutrakul, Rungtip Sumritsopak, Sunee Saetung, Suwannee Chanprasertyothin, La-Or Chailurkit, Thunyarat Anothaisintawee

Abstract

Objective: Melatonin, a neurohormone secreted by the pineal gland, controls circadian rhythmicity, modulates sleep and plays a role in glucose metabolism. Low secretion of nocturnal urinary 6-sulfatoxymelatonin (aMT6S) was associated with incident diabetes. Sleep disturbances have also been shown to be risk factors for diabetes. In this study, we explored the relationship between nocturnal urinary aMT6s and markers of glucose metabolism in prediabetes patients, considering sleep related factors.

Methods: Sixty two non-shift working patients with prediabetes [hemoglobin A1c (HbA1c) 5.7-6.49%] who were not on beta-blockers participated. Sleep duration and efficiency was recorded using 7-day actigraphy. Obstructive sleep apnea was evaluated using an overnight in-home monitoring device. Nocturnal urinary aMT6s/creatinine ratio was measured from an overnight urine sample. Oral glucose tolerance test (OGTT, 75-grams glucose) was performed, with measurements of insulin and glucose levels.

Results: Mean (SD) age was 55.3 (8.2) years and mean HbA1c level was 6.01 (0.2)%. Mean (SD) sleep duration 6.0 (0.9) h, sleep efficiency was 83.4 (6.6)% and a median (interquartile rage) apnea hypopnea index was 10.3 (3.6, 16.4). Median nocturnal urinary aMT6s was 17.4 (9.4, 28.2) ng/mg creatinine. Higher nocturnal urinary aMT6s significantly correlated with lower fasting insulin (p = 0.004), lower insulin response to OGTT (p = 0.027), and lower fasting and whole body insulin resistance as indicated by lower HOMA-IR and higher Matsuda insulin sensitivity index (p = 0.006 and p = 0.011, respectively), but it was not correlated with fasting glucose, glucose response to OGTT, or HbA1c. Sleep duration inversely correlated with HbA1c but no other correlations were found between other sleep variables and markers of glucose metabolism or nocturnal urinary aMT6s. After adjusting for body mass index, higher nocturnal urinary aMT6s significantly correlated with lower HOMA-IR (p = 0.025) and fasting insulin levels (p = 0.014).

Conclusion: Nocturnal urinary aMT6s inversely correlated with fasting insulin resistance and insulin levels in patients with prediabetes. These results support the role of melatonin in glucose metabolism.

Keywords: Glucose metabolism; Insulin; Insulin resistance; Melatonin; Prediabetes.

Figures

Fig. 1
Fig. 1
Correlation between nocturnal urinary aMT6s/Cr ratio and fasting insulin levels.
Fig. 2
Fig. 2
Correlation between nocturnal urinary aMT6s/Cr ratio and HOMA-IR.

References

    1. Agil A., Rosado I., Ruiz R., Figueroa A., Zen N., Fernandez-Vazquez G. Melatonin improves glucose homeostasis in young Zucker diabetic fatty rats. J. Pineal Res. 2012;52:203–210.
    1. American Diabetes Association: Standards of Medical Care in Diabetes, 2017. Diabetes Care 40:S1-S142, 2017.
    1. Anothaisintawee T., Reutrakul S., Van Cauter E., Thakkinstian A. Sleep disturbances compared to traditional risk factors for diabetes development: systematic review and meta-analysis. Sleep Med. Rev. 2015;30:11–24.
    1. Bonnefond A., Clement N., Fawcett K., Yengo L., Vaillant E., Guillaume J.L., 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 N.J., Sladek R., McCarthy M.I., Dina C., Barroso I., Jockers R., Froguel P. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat. Genet. 2012;44:297–301.
    1. Brzezinski A. Melatonin in humans. N. Engl. J. Med. 1997;336:186–195.
    1. Buxton O.M., Cain S.W., O’Connor S.P., Porter J.H., Duffy J.F., Wang W., Czeisler C.A., Shea S.A. Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci. Transl. Med. 2012;4:129ra43.
    1. Cagnacci A., Arangino S., Renzi A., Paoletti A.M., Melis G.B., Cagnacci P., Volpe A. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin. Endocrinol. 2001;54:339–346.
    1. Centers for Disease Control and Prevention. Diabetes Report Card, 2014.available at , accessed 2/1/2017, last updated 7-23-2015.
    1. Dallmann R., Viola A.U., Tarokh L., Cajochen C., Brown S.A. The human circadian metabolome. Proc. Natl. Acad. Sci USA. 2012;109:2625–2629.
    1. Eckel R.H., Depner C.M., Perreault L., Markwald R.R., Smith M.R., McHill A.W., Higgins J., Melanson E.L., Wright K.P., Jr Morning circadian misalignment during short sleep duration impacts insulin sensitivity. Curr. Biol. 2015;25:3004–3010.
    1. Faria J.A., Kinote A., Ignacio-Souza L.M., de Araujo T.M., Razolli D.S., Doneda D.L., Paschoal L.B., Lellis-Santos C., Bertolini G.L., Velloso L.A., Bordin S., Anhe G.F. Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats. Am. J Physiol. Endocrinol. Metab. 2013;305:E230–E242.
    1. Garaulet M., Gomez-Abellan P., Rubio-Sastre P., Madrid J.A., Saxena R., Scheer F.A. Common type 2 diabetes risk variant in MTNR1B worsens the deleterious effect of melatonin on glucose tolerance in humans. Metabolism. 2015;64:1650–1657.
    1. 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. 2011;4:307–313.
    1. Huang W., Ramsey K.M., Marcheva B., Bass J. Circadian rhythms, sleep, and metabolism. J. Clin. Investig. 2011;121:2133–2141.
    1. Kitagawa A., Ohta Y., Ohashi K. Melatonin improves metabolic syndrome induced by high fructose intake in rats. J. Pineal Res. 2012;52:403–413.
    1. Knowler W.C., Barrett-Connor E., Fowler S.E., Hamman R.F., Lachin J.M., Walker E.A., Nathan D.M. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 2002;346:393–403.
    1. Kozirog M., Poliwczak A.R., Duchnowicz P., Koter-Michalak M., Sikora J., Broncel M. Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome. J. Pineal Res. 2011;50:261–266.
    1. Leproult R., Holmback U., Van Cauter E. Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss. Diabetes. 2014;63:1860–1869.
    1. Matsuda M., DeFronzo R.A. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–1470.
    1. Matthews D.R., Hosker J.P., Rudenski A.S., Naylor B.A., Treacher D.F., Turner R.C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419.
    1. Mauriz J.L., Collado P.S., Veneroso C., Reiter R.J., Gonzalez-Gallego J. A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J. Pineal Res. 2013;54:1–14.
    1. McMullan C.J., Curhan G.C., Schernhammer E.S., Forman J.P. Association of nocturnal melatonin secretion with insulin resistance in nondiabetic young women. Am. J. Epidemiol. 2013;178:231–238.
    1. McMullan C.J., Schernhammer E.S., Rimm E.B., Hu F.B., Forman J.P. Melatonin secretion and the incidence of type 2 diabetes. JAMA. 2013;309:1388–1396.
    1. Mesri A.N., Mahdavi R., Roshanravan N., Lotfi Y.N., Ostadrahimi A.R., Faramarzi E. A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Horm. Metab. Res. 2015;47:504–508.
    1. Morikawa Y., Nakagawa H., Miura K., Soyama Y., Ishizaki M., Kido T., Naruse Y., Suwazono Y., Nogawa K. Shift work and the risk of diabetes mellitus among Japanese male factory workers. Scand. J. Work Environ. Health. 2005;31:179–183.
    1. Morris C.J., Aeschbach D., Scheer F.A. Circadian system, sleep and endocrinology. Mol. Cell Endocrinol. 2012;349:91–104.
    1. Morris C.J., Yang J.N., Garcia J.I., Myers S., Bozzi I., Wang W., Buxton O.M., Shea S.A., Scheer F.A. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans. Proc. Natl. Acad. Sci. USA. 2015;112:E2225–E2234.
    1. Morris C.J., Purvis T.E., Hu K., Scheer F.A. Circadian misalignment increases cardiovascular disease risk factors in humans. Proc. Natl. Acad. Sci. USA. 2016;113:E1402–E1411.
    1. Obayashi K., Saeki K., Iwamoto J., Ikada Y., Kurumatani N. Independent associations of exposure to evening light and nocturnal urinary melatonin excretion with diabetes in the elderly. Chronobiol. Int. 2014;31:394–400.
    1. de Oliveira A.C., Andreotti S., Farias T.S., Torres-Leal F.L., de Proenca A.R., Campana A.B., de Souza A.H., Sertie R.A., Carpinelli A.R., Cipolla-Neto J., Lima F.B. Metabolic disorders and adipose tissue insulin responsiveness in neonatally STZ-induced diabetic rats are improved by long-term melatonin treatment. Endocrinology. 2012;153:2178–2188.
    1. Pan A., Schernhammer E.S., Sun Q., Hu F.B. Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women. PLoS Med. 2011;8:e1001141.
    1. Peschke E., Muhlbauer E. New evidence for a role of melatonin in glucose regulation. Best Pract. Res. Clin. Endocrinol. Metab. 2010;24:829–841.
    1. Peschke E., Bahr I., Muhlbauer E. Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon. Int. J. Mol. Sci. 2013;14:6981–7015.
    1. Reutrakul S., Siwasaranond N., Nimitphong H., Saetung S., Chirakalwasan N., Chailurkit L.O., Srijaruskul K., Ongphiphadhanakul B., Thakkinstian A. Associations between nocturnal urinary 6-sulfatoxymelatonin, obstructive sleep apnea severity and glycemic control in type 2 diabetes. Chronobiol. Int. 2017;34:393–402.
    1. Rubio-Sastre P., Scheer F.A., Gomez-Abellan P., Madrid J.A., Garaulet M. Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep. 2014;37:1715–1719.
    1. Saksvik-Lehouillier I., Harrison S.L., Marshall L.M., Tranah G.J., Ensrud K., Ancoli-Israel S., Clemons A., Redline S., Stone K.L., Schernhammer E.S. Association of urinary 6-sulfatoxymelatonin (aMT6s) levels and objective and subjective sleep measures in Older men: the MrOS sleep study. J. Gerontol. A Biol. Sci. Med. Sci. 2015;70:1569–1577.
    1. Scheer F.A., Hilton M.F., Mantzoros C.S., Shea S.A. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc. Natl. Acad. Sci USA. 2009;106:4453–4458.
    1. Seltzer H.S., Allen E.W., Herron A.L., Jr., Brennan M.T. Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J. Clin. Investig. 1967;46:323–335.
    1. She M., Hou H., Wang Z., Zhang C., Laudon M., Yin W. Melatonin rescues 3T3-L1 adipocytes from FFA-induced insulin resistance by inhibiting phosphorylation of IRS-1 on Ser307. Biochimie. 2014;103:126–130.
    1. Shieh J.M., Wu H.T., Cheng K.C., Cheng J.T. Melatonin ameliorates high fat diet-induced diabetes and stimulates glycogen synthesis via a PKCzeta-Akt-GSK3beta pathway in hepatic cells. J. Pineal Res. 2009;47:339–344.
    1. Singh B., Saxena A. Surrogate markers of insulin resistance: a review. World J. Diabetes. 2010;1:36–47.
    1. Sparso T., Bonnefond A., Andersson E., Bouatia-Naji N., Holmkvist J., Wegner L., Grarup N., Gjesing A.P., Banasik K., Cavalcanti-Proenca C., Marchand M., Vaxillaire M., Charpentier G., Jarvelin M.R., Tichet J., Balkau B., Marre M., Levy-Marchal C., Faerch K., Borch-Johnsen K., Jorgensen T., Madsbad S., Poulsen P., Vaag A., Dina C., Hansen T., Pedersen O., Froguel P. 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 Europeans. Diabetes. 2009;58:1450–1456.
    1. Suwazono Y., Sakata K., Okubo Y., Harada H., Oishi M., Kobayashi E., Uetani M., Kido T., Nogawa K. Long-term longitudinal study on the relationship between alternating shift work and the onset of diabetes mellitus in male Japanese workers. J. Occup. Environ. Med. 2006;48:455–461.
    1. Teodoro B.G., Baraldi F.G., Sampaio I.H., Bomfim L.H., Queiroz A.L., Passos M.A., Carneiro E.M., Alberici L.C., Gomis R., Amaral F.G., Cipolla-Neto J., Araujo M.B., Lima T., Akira U.S., Silveira L.R., Vieira E. Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle. J. Pineal Res. 2014;57:155–167.
    1. Thomas A.P., Hoang J., Vongbunyong K., Nguyen A., Rakshit K., Matveyenko A.V. Administration of melatonin and metformin prevents deleterious effects of circadian disruption and obesity in male rats. Endocrinology. 2016;157:4720–4731.
    1. Tripathy D., Almgren P., Tuomi T., Groop L. Contribution of insulin-stimulated glucose uptake and basal hepatic insulin sensitivity to surrogate measures of insulin sensitivity. Diabetes Care. 2004;27:2204–2210.
    1. Tuomi T., Nagorny C.L., Singh P., Bennet H., Yu Q., Alenkvist I., Isomaa B., Ostman B., Soderstrom J., Pesonen A.K., 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. Increased melatonin signaling is a risk factor for type 2 diabetes. Cell Metab. 2016;23:1067–1077.
    1. Weiss R., Cali A.M., Dziura J., Burgert T.S., Tamborlane W.V., Caprio S. Degree of obesity and glucose allostasis are major effectors of glucose tolerance dynamics in obese youth. Diabetes Care. 2007;30:1845–1850.
    1. Wright K.P., Jr, Drake A.L., Frey D.J., Fleshner M., Desouza C.A., Gronfier C., Czeisler C.A. Influence of sleep deprivation and circadian misalignment on cortisol, inflammatory markers, and cytokine balance. Brain Behav. Immun. 2015;47:24–34.
    1. Yuceege M., Firat H., Demir A., Ardic S. Reliability of the Watch-PAT 200 in detecting sleep apnea in highway bus drivers. J. Clin. Sleep Med. 2013;9:339–344.
    1. Zephy D., Ahmad J. Type 2 diabetes mellitus: role of melatonin and oxidative stress. Diabetes Metab. Syndr. 2015;9:127–131.
    1. Zou D., Grote L., Peker Y., Lindblad U., Hedner J. Validation a portable monitoring device for sleep apnea diagnosis in a population based cohort using synchronized home polysomnography. Sleep. 2006;29:367–374.

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