The Effects of Melatonin Supplementation on Glycemic Control: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to clarify the effect of melatonin supplementation on glycemic control. Databases including PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched until July 30th, 2018. Two reviewers independently assessed study eligibility, extracted data, and evaluated the risk of bias for included trials. Heterogeneity among included studies was assessed using Cochran’s Q test and I-square (I²) statistic. Data were pooled using random-effect models and mean difference (MD) was considered as the overall effect size. Twelve trials out of 292 selected reports were identified eligible to be included in current meta-analysis. The pooled findings indicated that melatonin supplementation significantly reduced fasting glucose (MD=–6.34; 95% CI, –12.28, –0.40; p=0.04; I²: 65.0) and increased the quantitative insulin sensitivity check index (QUICKI) (MD=0.01; 95% CI, 0.00, 0.02; p=0.01; I²: 0.0). However, melatonin administration did not significantly influence insulin levels (MD=–1.03; 95% CI, –3.82, 1.77; p=0.47; I²: 0.53), homeostasis model assessment of insulin resistance (HOMA-IR) (MD=–0.34; 95% CI, –1.25, 0.58; p=0.37; I²: 0.37) or HbA1c levels (MD=–0.22; 95% CI, –0.47, 0.03; p=0.08; I²: 0.0). In summary, the current meta-analysis showed a promising effect of melatonin supplementation on glycemic control through reducing fasting glucose and increasing QUICKI, yet additional prospective studies are recommended, using higher supplementation doses and longer intervention period, to confirm the impact of melatonin on insulin levels, HOMA-IR and HbA1c.

Key words

melatonin - glycemic control - insulin resistance - meta-analysis

• References

• 1 Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87: 4-14
• 2 Neri S, Calvagno S, Mauceri B, Misseri M, Tsami A, Vecchio C, Mastrosimone G, Di Pino A, Maiorca D, Judica A, Romano G, Rizzotto A, Signorelli SS. Effects of antioxidants on postprandial oxidative stress and endothelial dysfunction in subjects with impaired glucose tolerance and type 2 diabetes. Eur J Nutr 2010; 49: 409-416
• 3 Wright Jr. E, Scism-Bacon JL, Glass LC. Oxidative stress in type 2 diabetes: The role of fasting and postprandial glycaemia. Int J Clin Pract 2006; 60: 308-314
• 4 Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414: 813-820
• 5 Folli F, Corradi D, Fanti P, Davalli A, Paez A, Giaccari A, Perego C, Muscogiuri G. The role of oxidative stress in the pathogenesis of type 2 diabetes mellitus micro- and macrovascular complications: Avenues for a mechanistic-based therapeutic approach. Curr Diabetes Rev 2011; 7: 313-324
• 6 Johnson EL. Glycemic variability in type 2 diabetes mellitus: Oxidative stress and macrovascular complications. Adv Exp Med Biol 2012; 771: 139-154
• 7 Korkmaz A, Topal T, Tan DX, Reiter RJ. Role of melatonin in metabolic regulation. Rev Endocr Metab Disord 2009; 10: 261-270
• 8 Korkmaz A, Ma S, Topal T, Rosales-Corral S, Tan DX, Reiter RJ. Glucose: a vital toxin and potential utility of melatonin in protecting against the diabetic state. Mol Cell Endocrinol 2012; 349: 128-137
• 9 Pevet P, Challet E. Melatonin: Both master clock output and internal time-giver in the circadian clocks network. J Physiol Paris 2011; 105: 170-182
• 10 Bazwinsky-Wutschke I, Muhlbauer E, Wolgast S, Peschke E. Transcripts of calcium/calmodulin-dependent kinases are changed after forskolin- or IBMX-induced insulin secretion due to melatonin treatment of rat insulinoma beta-cells (INS-1). Horm Metab Res 2009; 41: 805-813
• 11 Mesri Alamdari N, Mahdavi R, Roshanravan N, Lotfi Yaghin N, Ostadrahimi AR, 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
• 12 Ozkanlar S, Kara A, Sengul E, Simsek N, Karadeniz A, Kurt N. Melatonin Modulates the immune system response and inflammation in diabetic rats experimentally-induced by alloxan. Horm Metab Res 2016; 48: 137-144
• 13 Campino C, Valenzuela FJ, Torres-Farfan C, Reynolds HE, Abarzua-Catalan L, Arteaga E, Trucco C, Guzman S, Valenzuela GJ, Seron-Ferre M. Melatonin exerts direct inhibitory actions on ACTH responses in the human adrenal gland. Horm Metab Res 2011; 43: 337-342
• 14 Rios-Lugo MJ, Cano P, Jimenez-Ortega V, Fernandez-Mateos MP, Scacchi PA, Cardinali DP, Esquifino AI. 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
• 15 Kozirog M, Poliwczak AR, 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
• 16 Poon AM, Choy EH, Pang SF. Modulation of blood glucose by melatonin: A direct action on melatonin receptors in mouse hepatocytes. Biol Signals Recep 2001; 10: 367-379
• 17 Lima FB, Machado UF, Bartol I, Seraphim PM, Sumida DH, Moraes SM, Hell NS, Okamoto MM, Saad MJ, Carvalho CR, Cipolla-Neto J. Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats. Am J Physiol 1998; 275: E934-E941
• 18 Bahr I, Muhlbauer E, Schucht H, Peschke E. Melatonin stimulates glucagon secretion in vitro and in vivo. J Pineal Res 2011; 50: 336-344
• 19 Rezvanfar MR, Heshmati G, Chehrei A, Haghverdi F, Rafiee F, Rezvanfar F. Effect of bedtime melatonin consumption on diabetes control and lipid profile. Int J Diabetes Dev C. 2017; 37: 74-77
• 20 Raygan F, Ostadmohammadi V, Bahmani F, Reiter RJ, Asemi Z. 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 2017; pii: S0261-5614(17)31424-3.
• 21 Sun H, Wang X, Chen J, Gusdon AM, Song K, Li L, Qu S. Melatonin treatment improves insulin resistance and pigmentation in obese patients with acanthosis Nigricans. Int J Endocrinol 2018; 2304746
• 22 Xia Q, Chen ZX, Wang YC, Ma YS, Zhang F, Che W, Fu D, Wang XF. Association between the melatonin receptor 1B gene polymorphism on the risk of type 2 diabetes, impaired glucose regulation: A meta-analysis. PLoS One. 2012; 7: e50107
• 23 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: 359-364
• 24 McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP. Melatonin secretion and the incidence of type 2 diabetes. JAMA 2013; 309: 1388-1396
• 25 Espino J, Pariente JA, Rodriguez AB. Role of melatonin on diabetes-related metabolic disorders. World J Diabetes 2011; 2: 82-91
• 26 Peschke E. Melatonin, endocrine pancreas and diabetes. J Pineal Res 2008; 44: 26-40
• 27 Robeva R, Kirilov G, Tomova A, Kumanov P. Melatonin-insulin interactions in patients with metabolic syndrome. J Pineal Res 2008; 44: 52-56
• 28 Akbari M, Ostadmohammadi V, Tabrizi R, Lankarani KB, Heydari ST, Amirani E, Reiter RJ, Asemi Z. The effects of melatonin supplementation on inflammatory markers among patients with metabolic syndrome or related disorders: A systematic review and meta-analysis of randomized controlled trials. Inflammopharmacology 2018; 26: 899-907
• 29 D'Anna R, Santamaria A, Giorgianni G, Vaiarelli A, Gullo G, Di Bari F, Benvenga S. Myo-inositol and melatonin in the menopausal transition. Gynecol Endocrinol 2017; 33: 279-282
• 30 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: 33-38
• 31 Stebelova K, Anttila K, Manttari S, Saarela S, Zeman M. Immunohistochemical definition of MT(2) receptors and melatonin in the gastrointestinal tissues of rat. Acta Histochem 2010; 112: 26-33
• 32 Peschke E, Fauteck JD, Musshoff U, Schmidt F, Beckmann A, Peschke D. Evidence for a melatonin receptor within pancreatic islets of neonate rats: Functional, autoradiographic, and molecular investigations. J Pineal Res 2000; 28: 156-164
• 33 Peschke E, Stumpf I, Bazwinsky I, Litvak L, Dralle H, Muhlbauer E. Melatonin and type 2 diabetes - a possible link?. J Pineal Res 2007; 42: 350-358
• 34 Staiger H, Machicao F, Schafer SA, Kirchhoff K, Kantartzis K, Guthoff M, Silbernagel G, Stefan N, Haring HU, Fritsche A. Polymorphisms within the novel type 2 diabetes risk locus MTNR1B determine beta-cell function. PLoS One 2008; 3: e3962
• 35 Mussig K, Staiger H, Machicao F, Haring HU, Fritsche A. Genetic variants in MTNR1B affecting insulin secretion. Ann Med 2010; 42: 387-393
• 36 Kan MY, Zhou DZ, Zhang D, Zhang Z, Chen Z, Yang YF, Guo XZ, Xu H, He L, Liu Y. Two susceptible diabetogenic variants near/in MTNR1B are associated with fasting plasma glucose in a Han Chinese cohort. Diabet Med 2010; 27: 598-602
• 37 Contreras-Alcantara S, Baba K, Tosini G. Removal of melatonin receptor type 1 induces insulin resistance in the mouse. Obesity (Silver Spring) 2010; 18: 1861-1863
• 38 Agahi M, Akasheh N, Ahmadvand A, Akbari H, Izadpanah F. Effect of melatonin in reducing second-generation antipsychotic metabolic effects: A double blind controlled clinical trial. Diabetes Metab Syndr 2018; 12: 9-15
• 39 Ghaderi A, Banafshe HR, Mirhosseini N, Motmaen M, Mehrzad F, Bahmani F, Aghadavod E, Mansournia MA, Reiter RJ, Karimi MA, Asemi Z. The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment. Addict Biol 2018;
• 40 Goyal A, Terry PD, Superak HM, Nell-Dybdahl CL, Chowdhury R, Phillips LS, Kutner MH. Melatonin supplementation to treat the metabolic syndrome: A randomized controlled trial. Diabetol Metab Syndr 2014; 6: 124
• 41 Gonciarz M, Gonciarz Z, Bielanski W, Mularczyk A, Konturek PC, Brzozowski T, Konturek SJ. 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 2012; 63: 35-40
• 42 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: 1483-1488
• 43 Modabbernia A, Heidari P, Soleimani R, Sobhani A, Roshan ZA, Taslimi S, Ashrafi M, Modabbernia MJ. 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
• 44 Rezvanfar MR, Heshmati G, Chehrei A, Haghverdi F, Rafiee F, Rezvanfar F. Effect of bedtime melatonin consumption on diabetes control and lipid profile. Int J Diabetes Dev C 2017; 37: 74-77
• 45 Romo-Nava F, Alvarez-Icaza Gonzalez D, Fresan-Orellana A, Saracco Alvarez R, Becerra-Palars C, Moreno J, Ontiveros Uribe MP, Berlanga C, Heinze G, Buijs RM. Melatonin attenuates antipsychotic metabolic effects: An eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord 2014; 16: 410-421