Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study

Doron Garfinkel, Mariana Zorin, Julio Wainstein, Zipora Matas, Moshe Laudon, Nava Zisapel, Doron Garfinkel, Mariana Zorin, Julio Wainstein, Zipora Matas, Moshe Laudon, Nava Zisapel

Abstract

Background: Diabetes is a major comorbidity in insomnia patients. The efficacy and safety of prolonged-release melatonin 2 mg in the treatment of glucose, lipid metabolism, and sleep was studied in 36 type 2 diabetic patients with insomnia (11 men, 25 women, age 46-77 years).

Methods: In a randomized, double-blind, crossover study, the subjects were treated for 3 weeks (period 1) with prolonged-release melatonin or placebo, followed by a one-week washout period, and then crossed over for another 3 weeks (period 2) of treatment with the other preparation. All tablets were taken 2 hours before bedtime for a period of 3 weeks. In an extension period of 5 months, prolonged-release melatonin was given nightly to all patients in an open-label design. Sleep was objectively monitored in a subgroup of 22 patients using wrist actigraphy. Fasting glucose, fructosamine, insulin, C-peptide, triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol, and some antioxidants, as well as glycosylated hemoglobin (HbA1c) levels were measured at baseline and at the end of the study. All concomitant medications were continued throughout the study.

Results: No significant changes in serum glucose, fructosamine, insulin, C-peptide, antioxidant levels or blood chemistry were observed after 3 weeks of prolonged-release melatonin treatment. Sleep efficiency, wake time after sleep onset, and number of awakenings improved significantly with prolonged-release melatonin as compared with placebo. Following 5 months of prolonged-release melatonin treatment, mean HbA1c (±standard deviation) was significantly lower than at baseline (9.13% ± 1.55% versus 8.47% ± 1.67%, respectively, P = 0.005).

Conclusion: Short-term use of prolonged-release melatonin improves sleep maintenance in type 2 diabetic patients with insomnia without affecting glucose and lipid metabolism. Long-term prolonged-release melatonin administration has a beneficial effect on HbA1c, suggesting improved glycemic control.

Keywords: glucose; insulin; melatonin; sleep; type 2 diabetes.

Figures

Figure 1
Figure 1
Overall patient disposition. Analysis of the short-term period included eligible patients who completed three weeks of double-blind treatment with prolonged-release melatonin or placebo. Analysis of the long-term period included patients treated open-label with prolonged-release melatonin for 5 months. Analyses of actigraphic motion recordings included eligible patients who completed 3 weeks of treatment with prolonged-release melatonin and placebo and provided actigraphy data by the end of the treatment period. Abbreviation: PRM, prolonged-release melatonin.

References

    1. Narayan KM, Gregg EW, Fagot-Campagna A, Engelgau MM, Vinicor F. Diabetes: a common, growing, serious, costly, and potentially preventable public health problem. Diabetes Res Clin Pract. 2000;50(Suppl 2):S77–S84.
    1. Foley DJ, Monjan A, Simonsick EM, Wallace RB, Blazer DG. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep. 1999;22(Suppl 2):S366–S372.
    1. Chasens ER. Understanding sleep in persons with diabetes. Diabetes Educ. 2007;33(3):435–436.
    1. Gottlieb DJ, Punjabi NM, Newman AB, et al. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. 2005;165(8):863–867.
    1. Barone MT, Menna-Barreto L. Diabetes and sleep: a complex cause-and-effect relationship. Diabetes Res Clin Pract. 2011;91(2):129–137.
    1. Knutson KL, Van Cauter E, Zee P, Liu K, Lauderdale DS. Cross-sectional associations between measures of sleep and markers of glucose metabolism among subjects with and without diabetes: the Coronary Artery Risk Development in Young Adults (CARDIA) Sleep Study. Diabetes Care. 2011;34(5):1171–1176.
    1. Eriksson AK, Ekbom A, Granath F, Hilding A, Efendic S, Ostenson CG. Psychological distress and risk of pre-diabetes and type 2 diabetes in a prospective study of Swedish middle-aged men and women. Diabet Med. 2008;25(7):834–842.
    1. Cajochen C, Krauchi K, Wirz-Justice A. Role of melatonin in the regulation of human circadian rhythms and sleep. J Neuroendocrinol. 2003;15(4):432–437.
    1. Gorfine T, Assaf Y, Goshen-Gottstein Y, Yeshurun Y, Zisapel N. Sleep-anticipating effects of melatonin in the human brain. Neuroimage. 2006;31(1):410–418.
    1. Gorfine T, Zisapel N. Late evening brain activation patterns and their relation to the internal biological time, melatonin, and homeostatic sleep debt. Hum Brain Mapp. 2009;30(2):541–552.
    1. Sharma M, Palacios-Bois J, Schwartz G, et al. Circadian rhythms of melatonin and cortisol in aging. Biol Psychiatry. 1989;25(3):305–319.
    1. Leger D, Laudon M, Zisapel N. Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med. 2004;116(2):91–95.
    1. O’Brien IA, Lewin IG, O’Hare JP, Arendt J, Corrall RJ. Abnormal circadian rhythm of melatonin in diabetic autonomic neuropathy. Clin Endocrinol (Oxf) 1986;24(4):359–364.
    1. Sandyk R, Anastasiadis PG, Anninos PA, Tsagas N. Is the pineal gland involved in the pathogenesis of endometrial carcinoma. Int J Neurosci. 1992;62(1–2):89–96.
    1. Zisapel N. Sleep and sleep disturbances: biological basis and clinical implications. Cell Mol Life Sci. 2007;64(10):1174–1186.
    1. Nishida S. Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine. 2005;27(2):131–136.
    1. Korkmaz A, Reiter RJ, Topal T, Manchester LC, Oter S, Tan DX. Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med. 2009;15(1–2):43–50.
    1. Peschke E. Melatonin, endocrine pancreas and diabetes. J Pineal Res. 2008;44(1):26–40.
    1. Robeva R, Kirilov G, Tomova A, Kumanov P. Melatonin-insulin interactions in patients with metabolic syndrome. J Pineal Res. 2008;44(1):52–56.
    1. Prokopenko I, Langenberg C, Florez JC, et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet. 2009;41(1):77–81.
    1. Tam CH, Ho JS, Wang Y, et al. Common polymorphisms in MTNR1B, G6PC2 and GCK are associated with increased fasting plasma glucose and impaired beta-cell function in Chinese subjects. PLoS One. 2010;5(7):e11428.
    1. Mussig K, Staiger H, Machicao F, Haring HU, Fritsche A. Genetic variants in MTNR1B affecting insulin secretion. Ann Med. 2010;42(6):387–393.
    1. Waldhauser F, Waldhauser M, Lieberman HR, Deng MH, Lynch HJ, Wurtman RJ. Bioavailability of oral melatonin in humans. Neuroendocrinology. 1984;39(4):307–313.
    1. Wade A, Downie S. Prolonged-release melatonin for the treatment of insomnia in patients over 55 years. Expert Opin Investig Drugs. 2008;17(10):1567–1572.
    1. Luthringer R, Muzet M, Zisapel N, Staner L. The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. Int Clin Psychopharmacol. 2009;24(5):239–249.
    1. Wade AG, Ford I, Crawford G, et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med. 2010;8:51.
    1. Wade AG, Crawford G, Ford I, et al. Prolonged release melatonin in the treatment of primary insomnia: evaluation of the age cut-off for short- and long-term response. Curr Med Res Opin. 2011;27(1):87–98.
    1. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346(8974):541–544.
    1. Coniff RF, Shapiro JA, Robbins D, et al. Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. A placebo-controlled dose-comparison study. Diabetes Care. 1995;18(6):817–824.
    1. 1995. Wrist activity based monitoring of nocturnal sleep: validation of a novel scoring algorithm. Ninth annual meeting of the Associated Professional Sleep Societies, Nashville, TE.
    1. Cagnacci A, Arangino S, Renzi A, et al. Influence of melatonin administration on glucose tolerance and insulin sensitivity of post-menopausal women. Clin Endocrinol (Oxf) 2001;54(3):339–346.
    1. Hussain SA, Khadim HM, Khalaf BH, Ismail SH, Hussein KI, Sahib AS. Effects of melatonin and zinc on glycemic control in type 2 diabetic patients poorly controlled with metformin. Saudi Med J. 2006;27(10):1483–1488.
    1. Nishida S, Segawa T, Murai I, Nakagawa S. 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. 2002;32(1):26–33.
    1. Radziuk J, Pye S. Diurnal rhythm in endogenous glucose production is a major contributor to fasting hyperglycaemia in type 2 diabetes. Suprachiasmatic deficit or limit cycle behaviour? Diabetologia. 2006;49(7):1619–1628.
    1. Lenters-Westra E, Slingerland RJ. Hemoglobin A1c point-of-care assays; a new world with a lot of consequences! J Diabetes Sci Technol. 2009;3(3):418–423.
    1. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–412.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi