Effect of Bedtime Melatonin Administration in Patients With Type 2 Diabetes: A Triple-Blind, Placebo-Controlled, Randomized Trial

Document Type : Research article


1 Department Of Clinical Pharmacy, School Of Pharmacy, Shahid Beheshti University Of Medical Sciences, Tehran, Iran.

2 Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences

4 Internal Medicine Department, Endocrinology Division, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

5 Food Safety Research Center, Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

6 Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

7 Department of Çlinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.


Melatonin is widely available as over the counter product. Despite promising effects of melatonin supplementation on glycemic control, there is a significant heterogeneity between studies. The current study aimed at determining the effect of melatonin on fasting blood glucose (FBG), insulin resistance/sensitivity indices, glycosylated hemoglobin A1c (HbA1c), and high sensitivity C-reactive protein (hs-CRP) among type 2 diabetes mellitus (T2D) population during 8 weeks in a randomized, triple-blind, placebo-controlled trial. Thirty four subjects with the mean age ± standard deviation of 57.74 ± 8.57 years and 36 subjects with the mean age of 57.61 ± 9.11 years were allocated to 6 mg nightly melatonin and placebo groups, respectively. Melatonin and placebo groups were matched by age, gender, body mass index, and duration of diabetes. Also, there was no significant difference in laboratory findings except for HbA1c, which was lower in the placebo group (7.00±0.89% vs 7.60±1.47%, P=0.042). After trial completion, the increase of serum levels of melatonin was greater in the intervention than the placebo group (3.38±1.33 vs 0.94±1.28 ng/L, P=0.192). Moreover, compared to placebo group, among melatonin users, homeostasis model assessment of insulin resistance (HOMA1-IR) tended to be unfavorable at the end of follow-up [-0.51 (-1.76-0.81) vs. 0.28 (-1.24-1.74), P=0.20]; the similar trend was also shown for insulin sensitivity index (HOMA1-S) [2.33 (-3.59-12.46) vs. -2.33 (-10.61-9.16), P=0.148]. No differences were observed in FBG, HbA1C, and hs-CRP changes between the trial groups. The current study did not support the improving effect of melatonin on glucose homeostasis.


Main Subjects

(1) Hadaegh F, Bozorgmanesh MR, Ghasemi A,
Harati H, Saadat N and Azizi F. High prevalence
of undiagnosed diabetes and abnormal glucose
tolerance in the Iranian urban population: Tehran
Lipid and Glucose Study. BMC. Public. Health
(2008) 8: 176.
(2) Forouhi NG and Wareham NJ. Epidemiology of
diabetes. Medicine (Abingdon) (2014) 42: 698-702.
(3) Saadat N, Esmaily H, Abbasinazari M, Tohidi M,
Salamzadeh J, Hadaegh F, Tolabi M, KalantarHormozi M and Dibaj M. Does Twice-weekly
Cabergoline Improve Anthropometrical and
Biochemical Profiles in Prediabetes? A Randomized
Double-blind Clinical Trial Pilot Study. Iran. J.
Pharm. Res. (2015) 14: 77-86.
(4) Shaseb E, Tohidi M, Abbasinazari M, Khalili D,
Talasaz AH, Omrani H and Hadaegh F. The effect
of a single dose of vitamin D on glycemic status and
C-reactive protein levels in type 2 diabetic patients
with ischemic heart disease: a randomized clinical
trial. Acta Diabetol. (2016) 53: 575-82.
(5) Hardeland R, Cardinali DP, Srinivasan V, Spence
DW, Brown GM and Pandi-Perumal SR. Melatonin-
-a pleiotropic, orchestrating regulator molecule.
Prog. Neurobiol. (2011) 93: 350-84.
(6) Mulder H, Nagorny CLF, Lyssenko V and Groop
L. Melatonin receptors in pancreatic islets: 
Farrokhian A et al. / IJPR (2019), 18 (Special Issue): 258-268
Good morning to a novel type 2 diabetes gene.
Diabetologia. (2009) 52: 1240-9.
(7) Krauchi K, Cajochen C and Wirz-Justice A. A
relationship between heat loss and sleepiness: effects
of postural change and melatonin administration. J.
Appl. Physiol. (1985). (1997) 83: 134-9.
(8) McArthur AJ, Lewy AJ and Sack RL. Non-24-hour
sleep-wake syndrome in a sighted man: circadian
rhythm studies and efficacy of melatonin treatment.
Sleep (1996) 19: 544-53.
(9) Reiter RJ, Tan DX, Osuna C and Gitto E. Actions
of melatonin in the reduction of oxidative stress. A
review. J. Biomed. Sci. (2000) 7: 444-58.
(10) Masana MI, Doolen S, Ersahin C, Al-Ghoul
WM, Duckles SP, Dubocovich ML and Krause
DN. MT(2) melatonin receptors are present and
functional in rat caudal artery. J. Pharmacol. Exp.
Ther. (2002) 302: 1295-302.
(11) Pohanka M. Impact of melatonin on immunity: a
review. Cent. Eur. J. Med. (2013) 8: 369-76.
(12) Karamitri A and Jockers R. Melatonin in type 2
diabetes mellitus and obesity. Nat. Rev. Endocrinol.
(2019) 15: 105-25.
(13) Sharma S, Singh H, Ahmad N, Mishra P and Tiwari
A. The role of melatonin in diabetes: Therapeutic
implications. Arch. Endocrinol. Metab. (2015) 59:
(14) Peschke E and Muhlbauer E. New evidence for a
role of melatonin in glucose regulation. Best Pract.
Res. Clin. Endocrinol. Metab. (2010) 24: 829-41.
(15) Kupczyk D, Rybka J, Kedziora-Kornatowska K
and Kȩdziora J. Melatonin and oxidative stress in
elderly patients with type 2 diabetes. Pol. Merkur.
Lekarski. (2010) 28: 407-9.
(16) Zephy D and Ahmad J. Type 2 diabetes mellitus:
Role of melatonin and oxidative stress. Diabetes
Metab. Syndr. (2015) 9: 127-31.
(17) Korkmaz A, Ma S, Topal T, Rosales-Corral S, Tan
DX and Reiter RJ. Glucose: A vital toxin and
potential utility of melatonin in protecting against
the diabetic state. Mol. Cell. Endocrinol. (2012)
349: 128-37.
(18) Nishida S. Metabolic effects of melatonin on
oxidative stress and diabetes mellitus. Endocrine
(2005) 27: 131-6.
(19) Hussain SA, Khadim HM, Khalaf BH, Ismail SH,
Hussein KI and Sahib AS. Effects of melatonin and
zinc on glycemic control in type 2 diabetic patients
poorly controlled with metformin. Saudi Med. J.
(2006) 27: 1483-8.
(20) Summary of Revisions: Standards of Medical Care
in Diabetes—2018. Diabetes Care. (2018) 41: S4-
(21) Ghasemi A, Tohidi M, Derakhshan A, Hasheminia
M, Azizi F and Hadaegh F. Cut-off points
of homeostasis model assessment of insulin
resistance, beta-cell function, and fasting serum
insulin to identify future type 2 diabetes: Tehran
Lipid and Glucose Study. Acta Diabetol. (2015)
52: 905-15.
(22) Rezvanfar MR, Heshmati G, Chehrei A, Haghverdi
F, Rafiee F and Rezvanfar F. Effect of bedtime
melatonin consumption on diabetes control and
lipid profile. Int. J. Diabetes Dev. Ctries. (2017)
37: 74–7.
(23) Raygan F, Ostadmohammadi V, Bahmani F, Reiter
RJ and 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, placebocontrolled trial. Clin. Nutr. (2019) 38: 191-6.
(24) Doosti-Irani A, Ostadmohammadi V, Mirhosseini
N, Mansournia MA, Reiter RJ, Kashanian M,
Rahimi M, Razavi M and Asemi Z. The Effects of
Melatonin Supplementation on Glycemic Control:
A Systematic Review and Meta-Analysis of
Randomized Controlled Trials. Horm. Metab. Res.
(2018) 50: 783-90.
(25) Rubio-Sastre P, Scheer FA, Gomez-Abellan P,
Madrid JA and Garaulet M. Acute melatonin
administration in humans impairs glucose tolerance
in both the morning and evening. Sleep. (2014) 37:
(26) Goyal A, Terry PD, Superak HM, Nell-Dybdahl
CL, Chowdhury R, Phillips LS and Kutner MH.
Melatonin supplementation to treat the metabolic
syndrome: a randomized controlled trial. Diabetol.
Metab. Syndr. (2014) 6: 124.
(27) Gonciarz M, Bielanski W, Partyka R, Brzozowski T,
Konturek PC, Eszyk J, Celinski K, Reiter RJ, and
Konturek SJ. Plasma insulin, leptin, adiponectin,
resistin, ghrelin, and melatonin in nonalcoholic
steatohepatitis patients treated with melatonin. J.
Pineal. Res. (2013) 54: 154-61.
(28) Garfinkel D, Zorin M, Wainstein J, Matas Z,
Laudon M, and 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: 307-13.
(29) Ghaderi A, Banafshe HR, Mirhosseini N, Motmaen
M, Mehrzad F, Bahmani F, Aghadavod E,
Mansournia MA, Reiter RJ, Karimi MA and Asemi
Z. The effects of melatonin supplementation on
mental health, metabolic and genetic profiles in
patients under methadone maintenance treatment.
Addict. Biol. (2019) 24: 754-64.
(30) Akbari M, Ostadmohammadi V, Tabrizi R, Lankarani 
effect of melatonin in diabetes mellitus type 2
KB, Heydari ST, Amirani E, Reiter RJ and 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.
(31) Harpsoe NG, Andersen LP, Gogenur I and Rosenberg
J. Clinical pharmacokinetics of melatonin: a
systematic review. Eur. J. Clin. Pharmacol. (2015)
71: 901-9.
(32) Andersen LP, Werner MU, Rosenkilde MM, Harpsoe
NG, Fuglsang H, Rosenberg J and Gogenur
I. Pharmacokinetics of oral and intravenous
melatonin in healthy volunteers. BMC Pharmacol.
Toxicol. (2016) 17: 8.
(33) Abdi S, Abbasinazari M, Valizadegan G, Kamarei
M, Panahi Y, Sarafzadeh F and Pourhoseingholi
MA. Does the Addition of Melatonin to Quadruple
Therapy Increases the Eradication Rate of
Helicobacter pylori? A Double-Blind Randomized
Clinical Trial. J. clin. Diagn. Res. (2018) 12: FC12-
(34) Hamdieh M, Abbasinazari M, Badri T, SaberiIsfeedvajani M and Arzani G. The impact of
melatonin on the alleviation of cognitive impairment
during electroconvulsive therapy: A double-blind
controlled trial. Neurol. Psychiat. BR. (2017) 24: