Effects of Melatonin Supplementation on Insulin Levels and Insulin Resistance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Insulin resistance (IR) is a pivotal process in various metabolic diseases. The well-known treatment is lifestyle modification and medication therapy, which may result in poor compliance and side effects. Melatonin has been suggested to have a role in glucose metabolism, yet the results across studies have been inconsistent. Therefore, we performed a systematic review to evaluate the effects of melatonin supplementation on insulin levels and IR. We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, and identified randomized controlled trials (RCTs) published prior to August 2020. Articles were reviewed, selected and extracted by two reviewers independently. In total, 8 RCTs of 376 participants were included. Data were pooled using a random-effects model, with mean differences (MDs) and 95% confidence intervals (CIs). Our results showed that melatonin administration significantly reduced insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR), and increased the quantitative insulin sensitivity check index (QUICKI). We conclude that melatonin ameliorated hyperinsulinemia, insulin resistance, and insulin sensitivity, and the results are an update of a previous meta-analysis. Although more investigations are required, we clearly provide evidence for the use of melatonin as an adjuvant treatment for metabolic disorders involving IR.

Key words

melatonin - insulin resistance - insulin levels

Publication History

Received: 24 December 2020

Accepted after revision: 01 July 2021

Article published online:
08 September 2021

• References

• 1 Einhorn D, Reaven GM, Cobin RH. et al American college of endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003; 9: 237-252
• 2 Yaribeygi H, Farrokhi FR, Butler AE. et al Insulin resistance: review of the underlying molecular mechanisms. J Cell Physiol 2019; 234: 8152-8161
• 3 Lebovitz HE. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes 2001; 109: S135-S148
• 4 Nduhirabandi F, Du Toit EF, Blackhurst D. et al 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 2011; 50: 171-182
• 5 Leibowitz A, Peleg E, Sharabi Y. et al The role of melatonin in the pathogenesis of hypertension in rats with metabolic syndrome. Am J Hypertens 2008; 21: 348-351
• 6 Ríos-Lugo MJ, Cano P, Jiménez-Ortega V. et al Melatonin effect on plasma adiponectin, leptin, insulin, glucose, triglycerides and cholesterol in normal and high fat-fed rats. J Pineal Res 2010; 49: 342-348
• 7 Wolden-Hanson T, Mitton DR, McCants RL. et al Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology 2000; 141: 487-497
• 8 McMullan CJ, Schernhammer ES, Rimm EB. et al Melatonin secretion and the incidence of type 2 diabetes. JAMA 2013; 309: 1388-1396
• 9 Rasmussen DD, Boldt BM, Wilkinson CW. et al Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology 1999; 140: 1009-1012 Errata: 143: 1269
• 10 Dumont M, Paquet J. Progressive decrease of melatonin production over consecutive days of simulated night work. Chronobiol Int 2014; 31: 1231-1238
• 11 Mojaverrostami S, Asghari N, Khamisabadi M. et al The role of melatonin in polycystic ovary syndrome: A review. Int J Reprod Biomed 2019; 17: 865-882
• 12 Fonken LK, Weil ZM, Nelson RJ. Dark nights reverse metabolic disruption caused by dim light at night. Obesity (Silver Spring) 2013; 21: 1159-1164
• 13 Shabani A, Foroozanfard F, Kavossian E. et al Effects of melatonin administration on mental health parameters, metabolic and genetic profiles in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial. J Affect Disord 2019; 250: 51-56
• 14 Farrokhian A, Tohidi M, Ahanchi NS. et al Effect of bedtime melatonin administration in patients with type 2 diabetes: A triple-blind, placebo-controlled, randomized trial. Iran J Pharm Res 2019; 18: 258-268
• 15 Garfinkel D, Zorin M, Wainstein J. et al 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
• 16 Amstrup AK, Sikjaer T, Pedersen SB. et al 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) 2016; 84: 342-347
• 17 Doosti-Irani A, Ostadmohammadi V, Mirhosseini N. et al The effects of melatonin supplementation on glycemic control: a systematic review and meta-analysis of randomized controlled trials. Horm Metab Res 2018; 50: 783-790 Errata 2018; 50: e6
• 18 Moher D, Shamseer L, Clarke M. et al Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4: 1
• 19 Higgins JP, Altman DG, Gøtzsche PC. et al The Cochrane collaborationʼs tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928
• 20 Higgins JPT, TJ, Chandler J et al. Cochrane handbook for systematic reviews of interventions version 6.1 (updated September 2020). Cochrane, 2020. Available from: www.training.cochrane.org/handbook; 2020
• 21 Nishida S. Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine 2005; 27: 131-136
• 22 Peschke E. Melatonin, endocrine pancreas and diabetes. J Pineal Res 2008; 44: 26-40
• 23 Peschke E, Stumpf I, Bazwinsky I. et al Melatonin and type 2 diabetes - a possible link?. J Pineal Res 2007; 42: 350-358
• 24 Peschke E, Bach AG, Mühlbauer E. Parallel signaling pathways of melatonin in the pancreatic beta-cell. J Pineal Res 2006; 40: 184-191
• 25 Ramracheya RD, Muller DS, Squires PE. et al Function and expression of melatonin receptors on human pancreatic islets. J Pineal Res 2008; 44: 273-279
• 26 Frankel BJ, Strandberg MJ. Insulin release from isolated mouse islets in vitro: no effect of physiological levels of melatonin or arginine vasotocin. J Pineal Res 1991; 11: 145-148
• 27 DʼAnna R, Santamaria A, Giorgianni G. et al Myo-inositol and melatonin in the menopausal transition. Gynecol Endocrinol 2017; 33: 279-282
• 28 Modabbernia A, Heidari P, Soleimani R. et al Melatonin for prevention of metabolic side-effects of olanzapine in patients with first-episode schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res 2014; 53: 133-140
• 29 Matthews DR, Hosker JP, Rudenski AS. et al Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
• 30 Abood SJ, Abdulsahib WK, Hussain SA. et al Melatonin potentiates the therapeutic effects of metformin in women with metabolic syndrome. Sci Pharm 2020; 88: 28
• 31 Kedziora-Kornatowska K, Szewczyk-Golec K, Kozakiewicz M. et al Melatonin improves oxidative stress parameters measured in the blood of elderly type 2 diabetic patients. J Pineal Res 2009; 46: 333-337
• 32 Teodoro BG, Baraldi FG, Sampaio IH. et al Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle. J Pineal Res 2014; 57: 155-167
• 33 Cipolla-Neto J, Amaral FG, Afeche SC. et al Melatonin, energy metabolism, and obesity: a review. J Pineal Res 2014; 56: 371-381
• 34 Tan DX, Manchester LC, Fuentes-Broto L. et al Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev 2011; 12: 167-188
• 35 Stanford KI, Middelbeek RJ, Townsend KL. et al Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 2013; 123: 215-223
• 36 Shabani A, Foroozanfard F, Kavossian E. et al. Effects of melatonin administration on mental health parameters, metabolic and genetic profiles in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial.. J Affect Disord 2019; 250: 51-56
• 37 Raygan F, Ostadmohammadi V, Bahmani F. et al. Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial.. Clin Nutr 2019; 38 (01) 191-196
• 38 D'Anna R, Santamaria A, Giorgianni G. et al. Myo-inositol and melatonin in the menopausal transition. Gynecol Endocrinol. 2017; 33 (01) 279-282
• 39 Ghaderi A, Banafshe HR, Mirhosseini N. et al. The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment.. Addict Biol 2019; 24 (04) 754-764
• 40 Daneshvar Kakhaki R, Ostadmohammadi V, Kouchaki E. et al. Melatonin supplementation and the effects on clinical and metabolic status in Parkinson's disease: A randomized, double-blind, placebo-controlled trial.. Clin Neurol Neurosurg 2020; 195: 105-878
• 41 Ostadmohammadi V, Soleimani A, Bahmani F. et al. The effects of melatonin supplementation on parameters of mental health, glycemic control, markers of cardiometabolic risk, and oxidative Stress in diabetic hemodialysis patients: a randomized, double-blind, placebo-controlled trial.. J Ren Nutr 2020; 30 (03) 242-250