Abstract
Introduction
Melatonin, a neurohormone primarily known for its regulation of circadian rhythms, has recently received attention for its potential role in glucose metabolism. Several trials suggest that melatonin supplementation may influence glycemic control through mechanisms involving insulin sensitivity and oxidative stress. However, findings across studies remain inconsistent. This systematic review aimed to summarize current evidence on the effects of melatonin administration on blood glucose parameters in diverse adult populations.
Method
PubMed, Web of Science, Scopus, and Google Scholar were searched for eligible randomized controlled trials (RCTs) published up to July 2025. Weighted mean differences (WMD) were calculated for net changes in risk factors using random effects models.
Results
30 RCTs (with 31 arms) were included. melatonin supplementation significantly reduced fasting blood sugar (WMD = -2.66 mg/dl, 95%CI: -4.53 to -0.80, n = 27), insulin (WMD = -1.58 µIU/ml, 95%CI: -2.40 to -0.76, n = 16), HOMA-IR (WMD = -0.53, 95%CI: -0.85 to -0.20, n = 16), and improve Quantitative Insulin Sensitivity Check Index (QUICKI) (WMD = 0.01, 95%CI: 0.00 to 0.01, n = 7). No significant effects were observed on HbA1c (WMD = -0.45%, 95%CI: -0.94 to 0.04, n = 7).
Conclusion
The results of the present meta-analysis showed that melatonin supplementation could significantly improve fasting blood glucose, insulin, and HOMA-IR levels. However, no significant results were observed for HbA1c. However, the results obtained were highly heterogeneous, so the results should be interpreted with caution.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12986-025-01061-5.
Keywords: Melatonin, Blood glucose, Insulin, HbA1c, HOMA-IR, QUICKI, Diabetes
Introduction
Impaired glucose tolerance represents an early, prediabetic condition that often precedes type 2 diabetes mellitus [1]. Blood glycemic indices, including fasting blood glucose and glycated hemoglobin (HbA1c), are essential for diagnosing diabetes as well as identifying individuals at increased risk due to prediabetes or impaired glucose regulation [2, 3]. Maintaining optimal glycemic control is crucial because persistent hyperglycemia induces oxidative stress and inflammation, damaging blood vessels and vital organs, which leads to microvascular and macrovascular complications such as cardiovascular disease, nephropathy, neuropathy, and retinopathy [4, 5]. Therefore, early interventions to manage blood glucose levels are essential to prevent following health consequences. While lifestyle modifications alongside pharmacological treatments are standard approaches to managing blood glucose levels, side effects such as reduced long-term efficacy, gastrointestinal discomfort, and, in some cases, toxicity of these medications [6, 7] have fueled interest in alternative and complementary therapies.
Melatonin, or N-acetyl-5-methoxytryptamine, an endogenous indoleamine secreted by the pineal gland, plays an important role in regulating physiological processes in accordance with the body’s circadian rhythms [8]. Beyond its well-established sleep-regulating effects, melatonin has also showed beneficial effects on metabolic profiles and inhibition of adrenocorticotropic hormone responses [9–12]. Preclinical studies and observational human research indicate that melatonin supplementation might improve glycemic control, insulin sensitivity, blood pressure regulation, and lipid profiles [13, 14]. Mechanistically, melatonin regulates blood glucose by binding to receptors on hepatocytes [15]. It also modulates glucose uptake in adipocytes by influencing the expression of glucose transporters [16]. Additionally, it stimulates the secretion of glucagon, which plays a key role in glucose and insulin metabolism [17].
Recent meta-analyses of randomized controlled trials have yielded conflicting results on melatonin supplementation’s effect on glycemic control. Some studies report no significant impact on fasting blood glucose or insulin resistance among patients with polycystic ovary syndrome (PCOS) [18], while others find significant reductions in fasting blood glucose, HbA1c, and insulin resistance [19, 20]. Findings in type 2 diabetes mellitus are also inconsistent, with some showing HbA1c improvements but no effect on fasting glucose, pointing to a possibly dose- or duration-dependent response [21]. Earlier analyses also found improved insulin sensitivity indices but inconsistent changes in insulin levels, HOMA-IR, and HbA1c [22]. Given these contradictions and the lack of a comprehensive review including all adult populations, this study aims to systematically evaluate the dose-response effects of melatonin supplementation on glycemic indices using GRADE assessment and meta-analysis.
Method
Search strategy
This meta-analysis was conducted according to the PRISMA guidelines. PubMed, ISI Web of Science and Scopus databases were systematically searched for randomized controlled trials (RCTs) in English published up to 25 July 2025 that examined the effects of melatonin on glycemic indices, using appropriate MeSH terms and relevant keywords. Search terms were developed based on the PICOS framework, which included medical subject headings and general keywords to reflect target population (adults), intervention (melatonin (capsule or tablet)), comparator (placebo), primary outcomes (glycemic indices), and study design (randomized controlled trials). (Table S1). We additionally reviewed the reference lists of included studies, relevant reviews, and previous meta-analyses. Details of the search strategies applied in PubMed, SCOPUS and ISI Web of Science databases are given in the Supplementary Tables S2. To increase coverage, Google Scholar was screened using relevant search terms up to the 30th page of results. Each article was independently evaluated by two reviewers (M.M. and V.H). Any disagreements were resolved through discussion with a third party (S.H.). Besides, a ‘My NCBI’ email alert was set up in PubMed to record any newly published articles after the initial search. The study protocol has been registered in the International Register of Prospective Systematic Reviews (PROSPERO) with the following registration number (CRD420251114583).
Study selection
The following eligibility criteria were used to select studies: [1] controlled trials with a parallel or crossover design; [2] examining of blood glucose indices (fasting blood glucose, insulin, glycosylated hemoglobin A1c, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and QUICKI at baseline and end of intervention or changes in both intervention and control groups; [4] intervention duration of at least two weeks; and [5] carried out in individuals aged 18 and above. Studies that did not meet the eligibility criteria were omitted from this review. Studies were excluded if [1] the net effect of melatonin could not be determined; [2] Melatonin supplementation lasted less than two weeks; [3] studies were not randomized controlled trials; and [4] Insufficient data were available on glucose parameters at baseline or follow-up.
Data extraction
Two reviewers (M.M. and V.H.) independently assessed the eligible RCTs and extracted relevant data using a standardized electronic form. The recorded characteristics of the studies included the first author’s name, year of publication, study country, design, number of subjects in each group, and intervention characteristics including doses based on mg/dl, duration based on week, and participant characteristics (i.e., age, gender, and body mass index). Where studies used multiple (two-armed) control groups, each control group was analyzed separately. We also extracted mean and standard deviation (SD) values for glucose parameters at baseline and at the end of each study. If measurements were reported at multiple time points, only the final values at the end of the intervention period were included in the analysis. For studies that administered multiple doses of melatonin, each dose arm was considered as a separate entry in the meta-analysis.
Quality assessment
The Cochrane Risk of Bias Assessment Tool for Randomized Controlled Trials (RCTs) was used to evaluate the risk of bias of the included articles. Given the heterogeneity in reporting and structure, the updated RoB 2 tool was not applied. This tool includes seven criteria for assessing quality, including random sequence generation (selection bias), allocation sequence concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting of outcome (reporting bias), and other potential sources of bias. The risk of bias in each study was classified as low, high, or unclear [23].
Quantitative data synthesis and statistical analysis
We assessed the impact of melatonin supplementation on various glucose parameters, including fasting blood glucose (mg/dL), insulin concentrations (µIU/mL), HbA1c (%), HOMA-IR, and QUICKI. Effect sizes were expressed using the weighted mean difference (WMD) along with the corresponding 95% confidence intervals (CI). For both melatonin and control groups, mean and standard deviation (SD) values were extracted at baseline and post-intervention. Net changes within each group were calculated by subtracting the baseline values from the endpoint measurements. If the SDs for change scores were not reported, they were estimated using the formula: square root [(SD pre-intervention)2 + (SD post-intervention)2 - (2 R × SD pre-intervention – SD post-intervention)], assuming a moderate correlation coefficient (R) = 0.8 [24]. In cases where data were expressed as median and interquartile range (IQR), mean and SD values were estimated using standardized conversion formulas [25]. To approximate minimum and maximum values from IQR, the following equations were applied: median + 2 × (Q3-median) and B = median – 2 ×(median-Q1), where A, B, Q1, and Q3 are upper and lower ends of the range, upper and lower ends of the IQR, respectively. Where standard errors (SE) were reported, SDs were calculated using the formula: SD = SE×sqrt (n), where (n) is the number of individuals in each group. Plot digitizer software was used to extract data if the outcome variable was exclusively presented in graphical form. All analyses were performed using STATA software, version 17.0 (StataCorp LLC, College Station, TX, USA). Heterogeneity between studies was examined using the Cochrane test (with a significance level of (P < 0.1)) and quantitatively using the I² statistic. An I² value of ≥ 50% indicated significant heterogeneity between studies. To account for between-study variability, a random-effects model was employed to estimate pooled effect sizes. A sensitivity analysis by leave-one-out method was performed to assess how each study affected the overall pooled results [26]. Publication bias was explored using Egger’s regression test and visual funnel plot inspection [27]. To identify potential sources of heterogeneity, subgroup analyses were conducted based on dosage (< 8 mg mg/day vs. ≥ 8 mg/day), intervention duration (≤ 10 weeks vs. >10 weeks), BMI (>27 kg/m² vs. ≤ 27 kg/m²), and population type (diabetic vs. non-diabetic). The main reason for choosing a BMI of 27 instead of 25 or 30 is not only because many metabolic problems start at this cut off [28], but also because the studies were equally divided between the two groups. In addition, random effects meta-regression analyses were conducted to examine whether changes in dose and duration of intervention were associated with glycemic outcomes.
Results
Study selection
The literature search and screening process carried out in this systematic review is shown in Fig. 1. A total of 1512 articles were retrieved from the searches. Of these, 399 duplicates were removed, remained 1113 records for eligibility screening based on title and abstract. After removing 1014 articles, 99 articles were validated for full-text assessment. Based on the exclusion criteria, studies that did not have a control group, or the intervention period was less than 2 weeks, or insufficient information could be extracted from the study were excluded. One eligible study from Google Scholar was also included in the study [29]. Ultimately, 30 studies (31 effect sizes) with 1452 subjects measuring blood glycemic indices were included in this review.
Fig. 1.
Flow chart of literature search process
Characteristics of included studies
The main characteristics of included studies are shown in Table 1. Based on this data, sixteen studies were conducted in Iran [30–45], three studies in Denmark [46–48], two studies in Poland [49, 50], two studies in the United States [29, 51], and one study each in Brazil [52], Mexico [53], Italy [54], Iraq [55], Romania [56], Korea [57], and Germany [58]. Two studies have a randomized cross over design [29, 48], one has a randomized parallel three-armed design [43], one has a two-armed randomized crossover design [51], the remaining studies all have a randomized parallel design. Eight studies included exclusively female participants [34, 43, 45, 46, 48, 54, 55, 57], three included only male participants [33, 47, 52], and the remaining included both genders. The duration of taking the supplement varied from 4 to 48 weeks. The dose of melatonin received across studies ranged from 2 to 10 mg per day. A total of 1452 participants were included in the analysis (766 in the melatonin group and 724 in the control group). Participants’ ages ranged between from 25.57 to 67.7 and the BMI of the participants ranged between 23.6 and 40.24 kg/m2. Although BMI was not available for four studies [29, 50, 52, 56]. Nine of the study population were diabetic [29, 31, 35, 39, 40, 42, 44, 47, 56]. Three of the studies were conducted on healthy subjects [52], two of whom were night shift workers [48, 58]. The remaining subjects were selected from a wide range of diseases, as shown in Table 1.
Table 1.
Characteristics of studies that evaluated the effect of melatonin supplementation on blood glycemic indices
| Author, Year | Location | Design | Gender | Duration (week) | Enrolment, n | Intervention(n) | Control (n) | Age, mean |
Type of intervention | Type of placebo | Dose (mg/d) |
Population | BMI (Kg/m2) mean |
BaselineFBS (mg/dl) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Seabra et al. [52] | Brazil | RP | M:40 | 4 | 40 | 30 | 10 | Total: 29 | Capsule (Melatonin) | Capsule (Powder) | 10 | Healthy | NA | 88.3 |
| Gonciarz et al. [50] | Poland | RP | F: 13, M:18 | 4 | 31 | 16 | 15 | IN: 42.1, CL:40.5 | Capsule (Melatonin) | Capsule (Powder) | 10 | NASH | 28.6 | 89.27 |
| Gonciarz et al. [50] | Poland | RP | F:16, M:26 | 12 | 42 | 30 | 12 | IN: 41.5, CL:40.8 | Capsule (Melatonin) | Capsule (Powder) | 10 | NASH | NA | 80.15 |
| Grieco et al. [29] | USA |
RC Wash out: 6 weeks) |
F:10, M:4 | 6 | 14 | 7 | 7 | IN:52.5, CL:52.5 | Capsule (Melatonin) | Capsule (white flour) | 10 | T2DM | NA | 141.98 |
| Goyal, A. et al. [2013] | USA |
RC2A Wash out: 6 weeks) |
F:22, M:17 | 10 | 39 | 39 | 38 | IN:62.7, CL:57.6 | Capsule (Melatonin) | Capsule (lactose powder) | 8 | MetS | 34.6 | 102.2 |
| Romo-Nava, F. [53] | Mexico | RP | F:22, M:22 | 8 | 44 | 20 | 24 | IN:30.6, CL:28.6 | Capsule (Melatonin) | Capsule (Powder) | 5 | bipolar disorder and schizophrenia | 26.1 | 88.8 |
| Modabbernia, A. et al. [30] | Iran | RP | F: 11, M:25 | 8 | 36 | 18 | 18 | IN:32.7, CL:32.8 | Tablet (Melatonin) | Tablet (Powder) | 3 | Schizophrenia | 23.9 | 85.4 |
| Amstrup, A. K. et al. [46] | Denmark | RP | F: 72 | 48 | 72 | 37 | 35 | IN: 62.4, CL:62.9 | Capsule (Melatonin) | Capsule (Powder) | 2 | postmenopausal women | 23.6 | 96.55 |
| D’Anna, R. et al. [54] | Italy | RP | F:32 | 24 | 32 | 16 | 16 | IN:49.1, CL:48.7 | Capsule (Melatonin + myoinositol) | Capsule (myoinositol) | 3 | postmenopausal women | 26.7 | NA |
| Raygan, F. et al. [2017] | Iran | RP | F:33, M:27 | 12 | 60 | 30 | 30 | IN:67.7, CL:65.3 | Capsule (Melatonin) | Capsule (Powder) | 10 | T2DM with CHD | 30.4 | 170.9 |
| Agahi, M. et al. [32] | Iran | RP | F:49, M:51 | 8 | 100 | 50 | 50 | IN:37.4, CL:37.46 | Capsule (Melatonin) | Capsule (Powder) | 3 | Schizophrenia | 25.1 | NA |
| Ghaderi, A. et al. [33] | Iran | RP | M:54 | 12 | 54 | 26 | 28 | IN:42.5, CL:42.7 | Capsule (Melatonin) | Capsule (Powder) | 10 | patients under methadone maintenance treatment | 24.8 | 95.1 |
| Shabani, A. et al. [34] | Iran | RP | F:58 | 12 | 58 | 29 | 29 | IN:26.5, CL:26 | Capsule (Melatonin) | Capsule (Powder) | 10 | PCOS | 27.1 | 94.9 |
| Farrokhian, A. et al. [35] | Iran | RP | F:33, M:37 | 9 | 70 | 34 | 36 | IN:57.74, CL:57.61 | Tablet (Melatonin) | Tablet (Powder) | 6 | T2DM | 29.33 | 151.09 |
| Bahrami, M. et al. [36] | Iran | RP | F:24, M:46 | 12 | 70 | 36 | 34 | IN:42.5, CL:42.6 | Tablet (Melatonin) | Tablet (Powder) | 6 | MetS | 31 | 105.7 |
| Bahrami, M. et al. [37] | Iran | RP | F:14, M:31 | 12 | 45 | 24 | 21 | IN: 44, CL:37.71 | Tablet (Melatonin) | Tablet (Powder) | 6 | NAFLD | 29.46 | 103.25 |
| Daneshvar Kakhaki, R. et al. [38] | Iran | RP | F:19, M:32 | 12 | 51 | 25 | 26 | IN:64.4, CL:66.3 | Capsule (Melatonin) | Capsule (Powder) | 10 | Parkinson’s Disease | 25.1 | 100.6 |
| Abood, S. J. et al. [55] | Iraq | RP | F:35 | 12 | 35 | 20 | 15 | IN:45.8, CL:48.07 | Capsule (Melatonin) | Capsule (lactose powder) | 10 | MetS | 40.24 | 125.4 |
| Ostadmohammadi, V. et al. [39] | Iran | RP | F:15, M:38 | 12 | 53 | 26 | 27 | IN:65.6, CL:64.1 | Capsule (Melatonin) | Capsule (Powder) | 10 | T2DM Hemodialysis | 26.4 | 127.1 |
| Anton, D. M. et al. [56] | Romania | RP | F:21, M:29 | 8 | 50 | 25 | 25 | IN:53.24, CL:52.21 | Tablet (Melatonin) | Tablet (Powder) | 3 | T2DM | NA | > 126 |
| Bazyar, H. et al. [40] | Iran | RP | F:34, M:16 | 8 | 50 | 25 | 25 | IN:53.64, CL:51.52 | Capsule (Melatonin) | Capsule (Powder) | 3 | T2DM | 27.38 | 172.04 |
| Esalatmanesh, K. et al. [41] | Iran | RP | F:51, M:13 | 12 | 64 | 32 | 32 | IN:49.31, CL:49.44 | Capsule (Melatonin) | Capsule (Powder) | 3 | Rheumatoid arthritis | 27.29 | 106.19 |
| Satari, M. et al. [42] | Iran | RP | F:19, M:27 | 12 | 46 | 22 | 24 | IN:66.9, CL:64.3 | Capsule (Melatonin) | Capsule (Powder) | 10 | T2DM nephropathy | 28.8 | 138 |
| Alizadeh, M. et al. [43] (i) | Iran | RP3A | F:41 | 8 | 41 | 21 | 20 | IN:25.57, CL:26.2 | Tablet (Melatonin) | Tablet (Powder) | 6 | PCOS | 28.4 | 82.47 |
| Alizadeh, M. et al. [43] (ii) | Iran | RP3A | F:42 | 8 | 42 | 21 | 21 | IN:25.57, CL:25.57 | Tablet (Melatonin) | Tablet (magnesium oxide) | 6 | PCOS | 28.4 | 82.47 |
| Kim, Y. et al. [57] | Korea | RP | F:38 | 6 | 38 | 19 | 19 | IN:61, CL:61 | Capsule (Melatonin) | Capsule (Powder) | 2 | Insomnia | 24.9 | 98 |
| Lauritzen, E. S. et al. [47] | Denmark | RP | M:17 | 12 | 17 | 9 | 8 | IN:65, CL:62 | Capsule (Melatonin) | Capsule (Powder) | 10 | T2DM | 29 | 139.09 |
| Bazyar, H. et al. [44] | Iran | RP | F:22, M:22 | 8 | 44 | 22 | 22 | IN:53.72, CL:53.3 | Tablet (Melatonin) | Tablet (Powder) | 6 | T2DM | 27.21 | 173.59 |
| de Sousa, C. A. R. et al. [48] | Denmark |
RC Wash out: NA) |
F:46 | 12 | 46 | 23 | 23 | Total: 37.1 | Tablet (Melatonin) | Tablet (Powder) | 3 | Healthy night shift workers | 29.9 | 89.7 |
| Hannemann, J. et al. [58] | Germany | RP | F:11, M:13 | 12 | 24 | 12 | 12 | IN:38.3, CL:34.8 | Tablet (Melatonin) | Tablet (Powder) | 2 | Healthy night shift workers | 26.1 | 87.1 |
| Alamdari, Naimeh Mesri. et al. [45] | Iran | RP | F:44 | 6 | 44 | 22 | 22 | IN:33.86, CL:34.86 | Tablet (Melatonin) | Tablet (Powder) | 6 | Obese women | > 30 | 98.17 |
RP: Randomized Parallel design, RC: Randomized crossover design, RC2A: Randomized crossover two-armed design RP2/3A: Randomized Parallel two/three-armed design, BMI: Body Mass Index, F: Female, M: Male, NASH: nonalcoholic steatohepatitis, T2DM: Type 2 diabetes mellitus, MetS: Metabolic Syndrome, CHD: Coronary Heart Disease, PCOS: Polycystic Ovarian Syndrome, NAFLD: nonalcoholic fatty liver disease, FBS: fasting blood sugar
Quality assessment
Based on the Cochrane risk of bias assessment, high quality with low overall risk of bias was demonstrated for most of the included studies. However, six studies [29, 50–53, 55] reported moderate quality based on risk of bias assessment (Table S3).
Meta-analysis results
Effect of melatonin on blood glycemic indices
Effect of melatonin on fasting blood sugar
Pooled results from the random-effect model analysis revealed that melatonin supplementation can decrease FBS significantly (WMD = −2.66 mg/dl, 95%CI: −4.53 to −0.80, P = 0.005, n = 27 [29–48, 50–53, 55, 57]) (Fig. 2). Also, significant heterogeneity between studies was found (I2 = 52.9%, P = < 0.001). On the other hand, sensitivity analysis had no significant impact on the overall meta-analysis results or the observed heterogeneity for FBS (Figure S1). Based on the funnel plot, there was evidence of asymmetry between studies (Fig. 7a); however, Egger’s test findings showed no evidence of publication bias (Egger’s test p-value for FBS = 0.74). Subgroup analysis to investigate the effect of melatonin on fasting blood sugar showed that melatonin can reduce fasting blood sugar independent of diabetes (P = 0.010, P = 0.038). Results in other subgroups showed that this reduction effect remained significant at doses greater than or equal to 8 mg (P = 0.047), intervention duration less than or equal to 10 weeks (P = 0.046), and individuals with a BMI less than or equal to 27 (P = 0.004). Subgroup analyses also only observed a significant effect for individuals with fasting glucose levels above 100 mg/dl (P = 0.014) (Table 2).
Fig. 2.
Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of melatonin supplementation on Fasting Blood Glucose (mg/dL)
Fig. 7.
Funnel plots for the effect of melatonin supplementation on a) Fasting Blood Sugar, b) Insulin(µIU/ml), c) HbA1c (%), d) HOMA-IR, e) QUICK
Table 2.
Results of subgroup analysis of included randomizes controlled trials in meta-analysis of melatonin supplementation on glycemic indices
| Variable | FBS (mg/dl) | Insulin (µIU/ml) | HbA1c (%) | HOMA-IR | QUICKI |
|---|---|---|---|---|---|
|
Dose < 8 mg No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
15 −2.83(−5.73, 0.08) 0.057 60.8 0.001 |
8 1.12(−0.93, 3.18) 0.283 38.4 0.123 |
5 −0.44(−1.05, 0.17) 0.154 96.6 < 0.001 |
8 −0.14(−0.60, 0.31) 0.541 81.5 < 0.001 |
Not sufficient data |
|
Dose ≥ 8 mg No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
12 −2.47(−4.92, −0.03) 0.047 41.8 0.06 |
8 −2.16(−2.27, −1.57) < 0.001 35.2 0.147 |
2 −0.49(−0.86, −0.13) 0.009 0.00 0.481 |
8 −0.75(−1.06, −0.45) < 0.001 60.5 0.013 |
6 0.01(0.01, 0.01) < 0.001 86.7 < 0.001 |
|
Duration ≤ 10w No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
13 −3.12(−6.18, −0.06) 0.046 65.0 < 0.001 |
6 0.89(−4.62, 6.40) 0.753 79.6 < 0.001 |
4 −0.72(−1.31, −0.13) 0.017 86.9 < 0.001 |
6 −0.70(−1.81, 0.42) 0.220 83.5 < 0.001 |
Not sufficient data |
|
Duration > 10w No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
14 −2.27(−4.62, 0.08) 0.058 32.2 0.094 |
10 −1.73(−2.27, −1.20) < 0.001 31.5 0.157 |
3 −0.08(−0.40, 0.24) 0.631 73.1 0.024 |
10 −0.46(−0.80, −0.11) 0.009 86.7 < 0.001 |
7 0.01(0.00, 0.01) < 0.001 93.7 < 0.001 |
|
BMI (Kg/m 2 ) ≤ 27 No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
8 −3.07(−5.15, −0.99) 0.004 21.9 0.0255 |
5 −1.79(−2.95, −0.63) 0.002 39.8 0.156 |
2 −0.25(−0.83, 0.33) 0.393 83.6 0.013 |
7 −0.29(−0.69, 0.11) 0.159 88.2 < 0.001 |
4 0.00(−0.01, 0.01) 0.642 93.3 < 0.001 |
|
BMI (Kg/m2 ) >27 No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
16 −3.14(−6.58, 0.29) 0.073 65.2 < 0.001 |
11 −1.53(−2.64, −0.41) 0.007 68.5 < 0.001 |
3 −0.26(−0.79, 0.26) 0.329 77.00 0.013 |
9 −0.84(−1.39, −0.29) 0.003 72.00 < 0.001 |
3 0.01(+ 0.00, 0.02) 0.002 93.0 < 0.001 |
|
T2DM No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
8 −9.70(−17.12, −2.29) 0.010 48.3 0.060 |
4 −1.61(−3.26, 0.04) 0.055 67.2 0.027 |
5 −0.70(−1.18, −0.22) 0.004 83.8 < 0.001 |
4 −0.74(−1.46, −0.03) 0.042 69.8 0.019 |
3 0.01(0.01, 0.02) < 0.001 88.9 < 0.001 |
|
Non-T2DM No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
19 −1.91(−3.70, −0.11) 0.038 51.7 0.005 |
12 −1.53(−2.53, −0.52) 0.003 62.5 0.002 |
2 0.02(−0.10, 0.15) 0.719 20.10 0.263 |
12 −0.44(−0.79, −0.08) 0.016 85.50 < 0.001 |
4 0.00(−0.01, 0.01) 0.685 93.0 < 0.001 |
|
BaselineFBS (mg/dl) < 100 No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
12 −1.84 (−4.17, 0.99) 0.121 58.4 0.006 |
8 −1.83 (−4.02, 0.37) 0.103 67.2 0.003 |
2 0.02 (−0.10, 0.15) 0.719 20.1 0.263 |
10 −0.44 (−0.84, −0.05) 0.029 87.5 < 0.001 |
3 0.0 (−0.01, 0.01) 0.677 95.1 < 0.001 |
|
Baseline FBS (mg/dl) ≥ 100 No. of studies WMD (95%CI) P-value I2 (%) P-heterogeneity |
15 −3.96 (−7.11, −0.80) 0.014 44.4 0.033 |
8 −1.40 (−2.26, −0.54) 0.001 59.00 0.017 |
5 −0.70(−1.18, −0.22) 0.004 83.8 < 0.001 |
6 −0.67 (−1.13, −0.21) 0.004 57.7 0.038 |
4 0.01 (0.00, 0.02) 0.004 90.1 < 0.001 |
Effect of melatonin on insulin
The results from the random effect model analysis showed that melatonin supplementation was able to significantly reduce insulin concentrations (WMD = −1.58 µIU/ml, 95%CI: −2.40 to −0.76, P = < 0.001, n = 16 [30, 31, 33–35, 38, 39, 41–43, 45, 48, 50, 54, 55]) (Fig. 3). Also, the results indicate high heterogeneity between studies (I2: 61.9%, P = < 0.001). Performing leave-one-out method for sensitivity analysis showed that the overall results were not dependent on any of the studies (Figure S2). Regarding publication bias, neither the funnel plot (Fig. 7b) nor the Egger test provides significant evidence on the existence of publication bias (Egger’s test p-value for insulin = 0.54). After subgroup analysis, the results showed that this effect was independent of BMI (P = 0.002, P = 0.007), although after subgrouping based on dose, study duration, and diabetic and non-diabetic populations, a significant reduction effect remained only in doses ≥ 8 mg (P = < 0.001), intervention duration >10 weeks (P = < 0.001), and non-diabetic individuals (P = 0.003) and baseline FBS ≥ 100 mg/dl (P = 0.001) (Table 2).
Fig. 3.
Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of melatonin supplementation on insulin (µIU/ml)
Effect of melatonin on HbA1c
This meta-analysis result demonstrated that melatonin supplementation had no significant effect on HbA1c (WMD = −0.45%, 95%CI: −0.94 to 0.04, P = 0.069, n = 7 [29, 35, 39, 40, 46, 48, 56]) (Fig. 4), and also, high heterogeneity was observed among included studies (I2: 95.1%, P = < 0.001). The effect size for the impact of melatonin on HbA1c were robust in the leave-one-out sensitivity analysis, proposing the omission of each single trial did not have a significant effect on the result of meta-analyze (Figure S3). Although the asymmetry is clearly visible in the funnel plot (Fig. 7c), the Egger test for the presence of publication bias is not significant (Egger’s test p-value for HbA1c = 0.18). Subgroup analysis showed significant reductions in HbA1c in studies with supplement doses greater than or equal to 8 mg/day (P = 0.009), duration ≤ 10 weeks (P = 0.017), baseline FBS ≥ 100 mg/dl (0.004) and among participants with diabetes (P = 0.004).
Fig. 4.
Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of melatonin supplementation on HbA1c (%)
Effect of melatonin on HOMA-IR
The results of the cumulative effects meta-analysis show that melatonin supplementation can significantly reduce HOMA-IR (WMD = −0.53, 95%CI: −0.85 to −0.20, P = 0.001, n = 16 [30, 31, 33–35, 38, 39, 42, 43, 46, 48, 50, 55, 57, 58]) (Fig 5); also, high heterogeneity between studies has shown (I2: 95.1%, P = < 0.001). Sensitivity analysis showed that the overall result and heterogeneity were not sensitive to any study (Figure S4). Consistent with significant publication bias according to Egger’s test (P = 0.052), asymmetry was observed in the funnel plot (Fig. 7d). The results of subgroup analyses showed that the reduction effect remained significant only in groups receiving doses ≥ 8 mg (P = < 0.001), or intervention duration >10 weeks (P = 0.009) or individuals BMI greater than 27 (P = 0.003). However, this significant effect was not related to being diabetic or non-diabetic and baseline FBS status, and the reduction effect remained significant in all populations.
Fig. 5.
Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of melatonin supplementation on HOMA-IR
Effect of melatonin on QUICKI
Pooled results from the random-effect model analysis revealed that melatonin supplementation can improve QUICKI (WMD = 0.01, 95%CI: 0.00 to 0.01, P = 0.032, n = 7 [31, 33, 34, 38, 39, 42, 58]) (Fig. 6). The heterogeneity between studies is significantly high (I2: 93.7%, P = < 0.001). Also, the melatonin result on QUICKI is not sensitive to any single study (Figure S5). Based on the results of Egger’s test (P = 0.52), no significant effect of publication bias was observed, which is also seen in the funnel plot (Fig. 7e). All subgroup analysis results remained significant except for non-diabetic subjects and subjects with BMI ≤ 27 and baseline FBS < 100 mg/dl. However, due to the lack of data on the QUICKI, the results of subgroup analyses are not very reliable.
Fig. 6.
Forest plot detailing weighted mean difference and 95% confidence intervals (CIs) for the effect of melatonin supplementation on QUICKI
Non-linear dose-response analysis
The results of the dose-response analysis indicated a significant association between melatonin doses with changes in insulin concentration (P = 0.001; Table 3; Fig. 8b) and HOMA-IR (P = 0.003; Table 3; Fig. 8d). Also, a significant association between the duration of melatonin supplementation and changes in insulin concentration (P < 0.001; Table 3; Fig. 9b) was observed. Due to lack of data, this analysis was not performed on QUICKI.
Table 3.
Meta-regression between changes in glycemic indices and administered doses and intervention duration of melatonin
| Regression | Dose-Response | |||||||
|---|---|---|---|---|---|---|---|---|
| Dose (mg/d) | Duration (week) | Dose (mg/d) | Duration (week) | |||||
| Variables | Coefficient | p-value | Coefficient | p-value | Coefficient | p-value | Coefficient | p-value |
| FBS (mg/dl) | −0.02 | 0.851 | 0.12 | 0.540 | 24.90 | 0.648 | −2.60 | 0.641 |
| Insulin (µIU/ml) | −0.58 | 0.034 | 0.13 | 0.697 | 618.37 | 0.001 | 11.06 | < 0.001 |
| HbA1c (%) | −0.82 | 0.786 | 13.09 | 0.314 | 5.94 | 0.503 | 0.52 | 0.338 |
| HOMA-IR | −1.40 | 0.120 | 1.80 | 0.492 | 0.03 | 0.003 | 0.96 | 0.304 |
Fig. 8.
Non-linear dose-response relations between melatonin supplementation and absolute mean differences. Dose-response relations between dose (mg/day) and absolute mean differences in a) Fasting Blood Sugar (mg/dl), b) Insulin(µIU/ml), c) HbA1c (%), and d) HOMA-IR
Fig. 9.
Non-linear dose-response relations between melatonin supplementation and absolute mean differences. Dose-response relations between duration of intervention (week) and absolute mean differences in a) Fasting Blood Sugar (mg/dl), b) Insulin(µIU/ml), c) HbA1c (%), and d) HOMA-IR
Meta-regression analysis
The results of the meta-regression test showed that there was a significant relationship between insulin concentration and supplement dose (Table 3; Fig. 10). There was no significant relationship between melatonin dose and duration and other glycemic indices (Table 3, Figure S6 and S7).
Fig. 10.
Meta-regression plots of the association between mean changes in insulin concentration (µIU/mg) and dose of melatonin supplementation
GRADE analysis
The quality of evidence in this meta-analysis was assessed using the GRADE protocol. The quality of evidence was considered moderate in studies assessing the effect of melatonin supplementation on fasting blood glucose, insulin, HOMA-IR, and QUICKI. In addition, the quality of evidence was downgraded to low in studies assessing the effect of melatonin supplementation on HbA1c (Table S4).
Discussion
This systematic review and meta-analysis comprehensively investigated the effects of melatonin supplementation on blood glycemic indices, including fasting blood sugar (FBS), insulin, HbA1c, HOMA-IR, and QUICKI. The results of the current meta-analysis showed that melatonin supplementation could significantly reduce fasting blood glucose and insulin concentrations. It also significantly improved HOMA-IR and QUICKI; however, melatonin supplementation failed to reach a significant level for reducing HbA1c. Subgroup analyses based on dose indicated that a dose of 8 mg/day or higher was likely required to achieve significant results. However, the results for other subgroups showed different results for blood glucose factors. An interesting result obtained from subgroup analyses was that most blood glycemic indices were significantly reduced by melatonin in individuals with impaired glucose tolerance with FBS above 100 mg/dL. Our findings suggest that melatonin supplementation may have more pronounced effects on glycemic control in individuals with type 2 diabetes and those with elevated fasting glucose levels. These populations, who already experience impaired glucose regulation, appear to benefit most from melatonin’s potential effects on insulin sensitivity and metabolic balance. However, the overall analysis was characterized by considerable heterogeneity across studies. This variability is likely due to differences in baseline health status, intervention protocols, and study designs. While we conducted multiple subgroup analyses to account for these factors, interpretation of the pooled results is limited due to the diversity of populations and methods studied. Furthermore, our dose-response and meta-regression analyses were performed on the entire data set and did not include subgroup stratification. As such, while they provide insight into overall trends, they may not fully capture the subtle effects of melatonin on different metabolic profiles.
The observed reduction in HbA1c among diabetic patients receiving higher doses of melatonin may reflect greater metabolic responsiveness and the need for stronger or longer interventions to influence long-term glycemic markers. The significant reduction in HbA1c observed among diabetic patients receiving higher doses of melatonin may be attributed to its enhanced effects on insulin secretion, oxidative stress modulation, and circadian rhythm regulation—mechanisms that are particularly impaired in this population [21].
The findings of this study are generally in line with previous meta-analysis investigating the effects of melatonin supplementation on blood glycemic indices. Our results also are consistent with those of Delpino et al. [20], who reported significant reductions in fasting blood glucose and insulin resistance parameters and HbA1c following melatonin supplementation, although observing no significant effects on HbA1c, although our results did not observe a significant reduction in HbA1c, unlike this study. Similarly, a 2021 meta-analysis was performed by Li Y et al. demonstrated that melatonin supplementation significantly reduced insulin levels and HOMA-IR, and improved insulin sensitivity [19]. Our findings also support those of Abadi et al. [59], who observed that melatonin supplementation significantly improves fasting blood glucose, insulin levels, HbA1c, and HOMA-IR in patients with type 2 diabetes, especially at doses above 6 mg per day and with durations longer than 12 weeks. A systematic review by Lv et al. found that melatonin supplementation significantly lowered HbA1c levels in patients with type 2 diabetes, while it did not produce a significant effect on fasting blood glucose [21]. These differences in outcomes may be attributed to variations in study design, participant characteristics, intervention duration, and baseline metabolic status across the included trials. Overall, dietary interventions can modulate metabolic health through various mechanisms, including improvements in glycemic control, insulin sensitivity, and lipid metabolism. The magnitude and direction of these effects often depend on the specific dietary pattern, nutrient composition, duration of intervention, and individual metabolic characteristics. These findings highlight the importance of personalized nutritional strategies in managing metabolic disorders [60–64].
The mechanisms through which melatonin may exert its beneficial effects on glycemic control are likely multifactorial. Melatonin is a critical regulator of circadian rhythms and regulates insulin secretion by modulating this rhythm to lower blood glucose levels [65, 66]. Disruptions in this timing are linked to impaired glucose tolerance and increased diabetes risk [65, 67]. Hyperglycemia induces the production of mitochondrial reactive oxygen species (ROS), leading to oxidative stress, β-cell dysfunction, and diabetic complications [68–70]. Melatonin serves as a potent antioxidant and free radical scavenger, reducing oxidative stress and preserving β-cell function [69, 71]. Studies have demonstrated that melatonin supplementation reduces markers of oxidative DNA damage (like 8-OHdG), which is associated with better glycemic control [72, 73]. Melatonin influences blood glucose levels by activating its receptors, MTR1 and MTR2, in pancreatic islets, where it modulates blood glucose levels by balancing insulin secretion from β-cells and glucagon secretion from α-cells [74]. Through its receptors in the liver, melatonin appears to increase the liver’s ability to store glucose by increasing glycogen synthesis [75, 76]. It stimulates important proteins involved in insulin signaling, such as AKT and protein kinase C, which help improve glucose processing in the liver [75]. In skeletal muscle cells, melatonin activates the insulin receptor substrate 1 (IRS1)-PI3K-PKCζ pathway and increase glucose uptake by facilitating GLUT4 translocation to the cell membrane, thereby improving peripheral glucose utilization [77, 78]. On the other hand, by suppressing the cAMP-PKA signaling pathway, melatonin inhibits lipolysis in adipocytes, which helps reduce free fatty acid levels and improve insulin sensitivity [79]. Additionally, melatonin has been reported to suppress hepatic gluconeogenesis, thus reducing endogenous production of glucose and contributing to better blood glucose control [80]. These multifaceted effects on glucose metabolism work together to explain the clinical improvements seen in fasting glucose parameters and insulin resistance among individuals taking melatonin supplements.
The included studies involved diverse populations, ranging from healthy individuals to those with chronic conditions that may influence glycemic outcomes. This variability contributed to the substantial heterogeneity observed across analyses. While subgroup analyses were conducted to account for key metabolic differences, such as diabetes status, fasting glucose levels, and BMI, the interpretation of pooled results remains limited. This meta-analysis aimed to provide a comprehensive overview of current evidence, but the findings should be interpreted with caution. Further studies in more homogeneous populations are needed to confirm and refine these observations.
This study offers several notable strengths. To our knowledge, this is among the few meta-analyses specifically focusing on melatonin’s effects on glycemic indices, with broader inclusion criteria and updated evidence. Moreover, it incorporates a diverse range of subgroups, stratified by dosage, intervention duration, BMI, and diabetic status. The influence of dosage and intervention duration was further explored through dose-response and meta-regression analyses, enhancing the depth and precision of the findings. Also, unlike previous meta-analyses, we included studies that had more than 2 weeks of intervention, which better reflects the effects of melatonin on blood sugar indicators. Despite its significant strengths, this study has several limitations that deserve attention. First, the pooled estimates showed significant heterogeneity that persisted even after subgroup and sensitivity analyses, potentially limiting the generalizability of the findings. Second, although this meta-analysis provides a more comprehensive synthesis, previous reviews have also examined the effects of melatonin; therefore, it cannot be considered the first in this area.
Conclusion
The current results of this systematic review and meta-analysis study showed that melatonin intervention could significantly reduce fasting blood sugar, insulin, and HOMA-IR levels and have an improvement effect on QUICKI, but melatonin failed to show a statistically significant effect on HbA1c reduction. This meta-analysis highlights melatonin’s potential to improve glycemic control, especially in individuals with impaired glucose metabolism. While the pooled results show promise, substantial heterogeneity and limited interpretability warrant cautious interpretation. Melatonin was generally well-tolerated across studies, suggesting a favorable safety profile. These findings underscore the need for future high-quality trials to clarify its role, optimal dosing, and target populations.
Supplementary Information
Acknowledgment
The grammar and sentence fluency of this article were enhanced with the aid of an AI tool.
Abbreviations
- RCTs
Randomized controlled trials
- T2DM
Type 2 diabetes mellitus
- FBS
Fast blood Sugar
- HbA1c
Hemoglobin A1c
- HOMA-IR
Homeostatic model assessment for insulin resistance
- BMI
Body mass index
- QUICKI
Quantitative insulin sensitivity check index
Author contributions
MM: Conceptualization, Data collection, Validation of results, data analysis, writing original and final draft version, review & editing, VH: Data collection, SH: Data collection, BJ and SA: Review and editing.
Funding
There is no fund for this study.
Data availability
The datasets generated and/or analyzed during the current study are not publicly available due confidential and private information but are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
No ethical statement was required for this study, no human or animal subjects or materials were used.
Consent for publication
Not applicable.
PROSPERO registration
The protocol of the study was registered in the International Prospective Register of Systematic Reviews (PROSPERO registration no: CRD420251114583).
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Milad Mohammadzadeh co-first author.
Contributor Information
Saeid Hadi, Email: Dr.saedhadi@gmail.com.
Milad Mohammadzadeh, Email: Milad.mohammadzadeh98@gmail.com.
References
- 1.Fonseca VA. Identification and treatment of prediabetes to prevent progression to type 2 diabetes. Clin Cornerstone. 2007;8(2):10–8. discussion 9–20. [DOI] [PubMed] [Google Scholar]
- 2.Akter S, Rahman MM, Abe SK, Sultana P. Prevalence of diabetes and prediabetes and their risk factors among Bangladeshi adults: a nationwide survey. Bull World Health Organ. 2014;92:204–A13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Tabák AG, Herder C, Rathmann W, Brunner EJ, Kivimäki M. Prediabetes: a high-risk state for developing diabetes. Lancet. 2012;379(9833):2279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Zakir M, Ahuja N, Surksha MA, Sachdev R, Kalariya Y, Nasir M et al. Cardiovascular complications of diabetes: from microvascular to macrovascular pathways. Cureus. 2023;15(9):e45835. [DOI] [PMC free article] [PubMed]
- 5.Alqahtani AA, Alzidany A, Alenazi S, Dhifallah T, Alotaibi B. Long term complication of poor glycemic control in diabetic patients. EC Microbiol. 2020;2:1–7. [Google Scholar]
- 6.Marín-Peñalver JJ, Martín-Timón I, Sevillano-Collantes C, del Cañizo-Gómez FJ. Update on the treatment of type 2 diabetes mellitus. World journal of diabetes. 2016;7(17):354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Salehi B, Ata A, Anil Kumar V, Sharopov N, Ramirez-Alarcon F, Ruiz-Ortega K. Antidiabetic potential of medicinal plants and their active components. Biomolecules. 2019;9(10):551. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pevet P, Challet E. Melatonin: both master clock output and internal time-giver in the circadian clocks network. Journal of Physiology-Paris. 2011;105(4–6):170–82. [DOI] [PubMed] [Google Scholar]
- 9.Campino C, Valenzuela F, Torres-Farfan C, Reynolds H, Abarzua-Catalan L, Arteaga E, et al. Melatonin exerts direct inhibitory actions on ACTH responses in the human adrenal gland. Horm Metab Res. 2011;43(05):337–42. [DOI] [PubMed] [Google Scholar]
- 10.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(02):137–44. [DOI] [PubMed] [Google Scholar]
- 11.Bazwinsky-Wutschke I, Mühlbauer 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 β-cells (INS-1). Horm Metab Res. 2009;41(11):805–13. [DOI] [PubMed] [Google Scholar]
- 12.Alamdari NM, Mahdavi R, Roshanravan N, Yaghin NL, Ostadrahimi A, 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(07):504–8. [DOI] [PubMed] [Google Scholar]
- 13.Ríos-Lugo MJ, Cano P, Jiménez‐Ortega V, Fernández‐Mateos MP, Scacchi PA, Cardinali DP, 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(4):342–8. [DOI] [PubMed] [Google Scholar]
- 14.Koziróg 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(3):261–6. [DOI] [PubMed] [Google Scholar]
- 15.Poon A, Choy E, Pang S. Modulation of blood glucose by melatonin: a direct action on melatonin receptors in mouse hepatocytes. Neurosignals. 2001;10(6):367–79. [DOI] [PubMed] [Google Scholar]
- 16.Lima FB, Machado UF, Bartol I, Seraphim PM, Sumida DH, Moraes SM, et al. Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats. Am J Physiol Endocrinol Metab. 1998;275(6):E934–41. [DOI] [PubMed]
- 17.Bähr I, Mühlbauer E, Schucht H, Peschke E. Melatonin stimulates glucagon secretion in vitro and in vivo. J Pineal Res. 2011;50(3):336–44. [DOI] [PubMed] [Google Scholar]
- 18.Ziaei S, Hasani M, Malekahmadi M, Daneshzad E, Kadkhodazadeh K, Heshmati J. Effect of melatonin supplementation on cardiometabolic risk factors, oxidative stress and hormonal profile in PCOS patients: a systematic review and meta-analysis of randomized clinical trials. J Ovarian Res. 2024;17(1):138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Li Y, Xu Z. Effects of melatonin supplementation on insulin levels and insulin resistance: a systematic review and meta-analysis of randomized controlled trials. Horm Metab Res. 2021;53(9):616–24. [DOI] [PubMed] [Google Scholar]
- 20.Delpino FM, Figueiredo LM, Nunes BP. Effects of melatonin supplementation on diabetes: a systematic review and meta-analysis of randomized clinical trials. Clin Nutr. 2021;40(7):4595–605. [DOI] [PubMed] [Google Scholar]
- 21.Lv X, Sun H, Ai S, Zhang D, Lu H. The effect of melatonin supplementation on glycemic control in patients with type 2 diabetes. Front Endocrinol (Lausanne). 2025;16:1572613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Doosti-Irani A, Ostadmohammadi V, Mirhosseini N, Mansournia MA, Reiter RJ, Kashanian M, 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(11):783–90. [DOI] [PubMed] [Google Scholar]
- 23.Higgins J. Cochrane handbook for systematic reviews of interventions. Version 5.1. 0 [updated March 2011]. The Cochrane Collaboration. www cochrane-handbook org. 2011.
- 24.Jpt H. Cochrane handbook for systematic reviews of interventions. http://www.cochrane-handbook.org. 2008.
- 25.Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Tobias A. Assessing the influence of a single study in the meta-analysis estimate. Stata Tech Bull. 1999;47:15–7. [Google Scholar]
- 27.Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Potter AW, Chin GC, Looney DP, Friedl KE. Defining overweight and obesity by percent body fat instead of body mass index. J Clin Endocrinol Metab. 2024;110(4):e1103-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Grieco CR, Colberg SR, Somma CT, Thompson AG, Vinik AI. Melatonin supplementation improves glycemic control while Lowering oxidative stress in type 2 diabetes. Int J Diabetes Res. 2013;2(3):45–9. [Google Scholar]
- 30.Modabbernia A, Heidari P, Soleimani R, Sobhani A, Roshan ZA, Taslimi S, 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;53:133–40. [DOI] [PubMed] [Google Scholar]
- 31.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. 2019;38(1):191–6. [DOI] [PubMed] [Google Scholar]
- 32.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(1):9–15. [DOI] [PubMed] [Google Scholar]
- 33.Ghaderi A, Banafshe HR, Mirhosseini N, Motmaen M, Mehrzad F, Bahmani F, et al. The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment. Addict Biol. 2019;24(4):754–64. [DOI] [PubMed] [Google Scholar]
- 34.Shabani A, Foroozanfard F, Kavossian E, Aghadavod E, Ostadmohammadi V, Reiter RJ, 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;250:51–6. [DOI] [PubMed] [Google Scholar]
- 35.Farrokhian A, Tohidi M, Ahanchi NS, Khalili D, Niroomand M, Mahboubi A, 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(Suppl1):258–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Bahrami M, Cheraghpour M, Jafarirad S, Alavinejad P, Cheraghian B. The role of melatonin supplement in metabolic syndrome a randomized double blind clinical trial. Nutr Food Sci. 2019;49(5):965–77. [Google Scholar]
- 37.Bahrami M, Cheraghpour M, Jafarirad S, Alavinejad P, Asadi F, Hekmatdoost A, et al. The effect of melatonin on treatment of patients with non-alcoholic fatty liver disease: a randomized double blind clinical trial. Complement Ther Med. 2020;52:102452. [DOI] [PubMed] [Google Scholar]
- 38.Daneshvar Kakhaki R, Ostadmohammadi V, Kouchaki E, Aghadavod E, Bahmani F, Tamtaji OR, 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;195:105878. [DOI] [PubMed] [Google Scholar]
- 39.Ostadmohammadi V, Soleimani A, Bahmani F, Aghadavod E, Ramezani R, Reiter RJ, 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(3):242–50. [DOI] [PubMed] [Google Scholar]
- 40.Bazyar H, Javid AZ, Behbahani HB, Moradi F, Poode BM, Amiri P. Consumption of melatonin supplement improves cardiovascular disease risk factors and anthropometric indices in type 2 diabetes mellitus patients: a double-blind, randomized, placebo-controlled trial. Trials. 2021;22(1):231. [DOI] [PMC free article] [PubMed]
- 41.Esalatmanesh K, Loghman A, Esalatmanesh R, Soleimani Z, Khabbazi A, Mahdavi AM, et al. Effects of melatonin supplementation on disease activity, oxidative stress, inflammatory, and metabolic parameters in patients with rheumatoid arthritis: a randomized double-blind placebo-controlled trial. Clin Rheumatol. 2021;40(9):3591–7. [DOI] [PubMed] [Google Scholar]
- 42.Satari M, Bahmani F, Reiner Z, Soleimani A, Aghadavod E, Kheinpour N, et al. Metabolic and Anti-inflammatory response to melatonin administration in patients with diabetic nephropathy. Iran J Kidney Dis. 2021;15(1):22–30. [PubMed] [Google Scholar]
- 43.Alizadeh M, Karandish M, Jafarabadi MA, Heidari L, Nikbakht R, Rezaei HB, et al. Metabolic and hormonal effects of melatonin and/or magnesium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Nutr Metab. 2021;18(1):57. [DOI] [PMC free article] [PubMed]
- 44.Bazyar H, Javid AZ, Zakerkish M, Yousefimanesh HA, Haghighi-Zadeh MH. Effects of melatonin supplementation in patients with type 2 diabetes mellitus and chronic periodontitis under nonsurgical periodontal therapy: a double-blind randomized controlled trial. J Res Med Sci. 2022;27:52. [DOI] [PMC free article] [PubMed]
- 45.Alamdari NM, Shabestari AN, Najafipour F, Mirmazhari A. Melatonin supplementation improves glycemic hemostasis, lipid profile, and adipokine concentrations of obese women: a double-blind randomized clinical trial. Biomed Adv. 2024;1(1):27–33. [Google Scholar]
- 46.Amstrup AK, Sikjaer T, Pedersen SB, Heickendorff L, Mosekilde L, Rejnmark L. 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. 2016;84(3):342–7. [DOI] [PubMed] [Google Scholar]
- 47.Lauritzen ES, Kampmann U, Pedersen MGB, Christensen LL, Jessen N, Moller N et al. Three months of melatonin treatment reduces insulin sensitivity in patients with type 2 diabetes-A randomized placebo-controlled crossover trial. J Pineal Res. 2022;73(1):e12809. [DOI] [PMC free article] [PubMed]
- 48.de Sousa CAR, Nogueira LF, Cipolla-Neto J, Moreno CRC, Marqueze EC. 12-week melatonin administration had no effect on diabetes risk markers and fat intake in overweight women night workers. Front Nutr. 2024;11:1285398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Gonciarz M, Gonciarz Z, Bielanski W, Mularczyk A, Konturek PC, Brzozowski T, et al. The pilot study of 3-month course of melatonin treatment of patients with nonalcoholic steatohepatitis: effect on plasma levels of liver enzymes, lipids and melatonin. J Physiol Pharmacology: Official J Pol Physiological Soc. 2010;61(6):705–10. [PubMed] [Google Scholar]
- 50.Gonciarz M, Bielanski W, Partyka R, Brzozowski T, Konturek PC, Eszyk J, et al. Plasma insulin, leptin, adiponectin, resistin, ghrelin, and melatonin in nonalcoholic steatohepatitis patients treated with melatonin. J Pineal Res. 2013;54(2):154–61. [DOI] [PubMed] [Google Scholar]
- 51.Goyal A, Terry PD, Superak HM, Nell-Dybdahl CL, Chowdhury R, Phillips LS, et al. Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial. Diabetol Metab Syndr. 2014;6:124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Seabra ML, Bignotto M, Pinto LR Jr., Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29(4):193–200. [DOI] [PubMed] [Google Scholar]
- 53.Romo-Nava F, Alvarez-Icaza González D, Fresán-Orellana A, Saracco Alvarez R, Becerra-Palars C, Moreno J, et al. Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord. 2014;16(4):410–21. [DOI] [PubMed] [Google Scholar]
- 54.D’Anna R, Santamaria A, Giorgianni G, Vaiarelli A, Gullo G, Di Bari F, et al. Myo-inositol and melatonin in the menopausal transition. Gynecol Endocrinol. 2017;33(4):279–82. [DOI] [PubMed] [Google Scholar]
- 55.Abood SJ, Abdulsahib WK, Hussain SA, Ismail SH. Melatonin potentiates the therapeutic effects of metformin in women with metabolic syndrome. Scient Pharm. 2020;88(2):28.
- 56.Anton DM, Martu MA, Maris M, Maftei GA, Sufaru IG, Tatarciuc D, et al. Study on the effects of melatonin on glycemic control and periodontal parameters in patients with type II diabetes mellitus and periodontal disease. Medicina (Kaunas, Lithuania). 2021;57(2):140. [DOI] [PMC free article] [PubMed]
- 57.Kim Y, Kang HT, Lee DC. Melatonin supplementation for six weeks had no effect on arterial stiffness and mitochondrial DNA in women aged 55 years and older with insomnia: a double-blind randomized controlled study. Int J Environ Res Public Health. 2021;18(5):2561. [DOI] [PMC free article] [PubMed]
- 58.Hannemann J, Laing A, Middleton B, Schwedhelm E, Marx N, Federici M, et al. Effect of oral melatonin treatment on insulin resistance and diurnal blood pressure variability in night shift workers. A double-blind, randomized, placebo-controlled study. Pharmacol Res. 2024;199:107011. [DOI] [PubMed] [Google Scholar]
- 59.Abadi RNS, Jazinaki MS, Bahari H, Rashidmayvan M, Amini MR, Aliakbarian M, et al. Impact of melatonin supplementation on glycemic parameters in patients with type 2 diabetes: a systematic review and meta-analysis. Curr Pharm Des. 2025;31(8):645–57. [DOI] [PubMed] [Google Scholar]
- 60.Morvaridi M, Rayyani E, Jaafari M, Khiabani A, Rahimlou M. The effect of green coffee extract supplementation on cardio metabolic risk factors: a systematic review and meta-analysis of randomized controlled trials. J Diabetes Metab Disord. 2020;19(1):645–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Mousavi SN, Rayyani E, Heshmati J, Tavasolian R, Rahimlou M. Effects of Ramadan and non-ramadan intermittent fasting on gut microbiome. Front Nutr. 2022;9:860575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Rahimlou M, Grau N, Banaie-Jahromi N, Taheri M, Khosravi A, Mavrommatis Y, et al. Association of adherence to the dietary approach to stop hypertension and Mediterranean diets with blood pressure in a non-hypertensive population: results from Isfahan Salt Study (ISS). Nutr Metab Cardiovasc Dis. 2022;32(1):109–16. [DOI] [PubMed] [Google Scholar]
- 63.Mohammadzadeh M, Amirpour M, Ahmadirad H, Abdi F, Khalesi S, Naghshi N, et al. Impact of fasting mimicking diet (FMD) on cardiovascular risk factors: a systematic review and meta-analysis of randomized control trials. Diabetol Metab Syndr. 2025;17(1):137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Abdi F, Mohammadzadeh M, Abbasalizad-Farhangi M. Dietary amino acid patterns and cardiometabolic risk factors among subjects with obesity; a cross-sectional study. BMC Endocr Disord. 2024;24(1):21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Goncharova N, Vengerin A, Khavinson VK, Lapin B. Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas. Exp Gerontol. 2005;40(1–2):51–7. [DOI] [PubMed] [Google Scholar]
- 66.Peschke E, Frese T, Chankiewitz E, Peschke D, Preiss U, Schneyer U, et al. Diabetic Goto Kakizaki rats as well as type 2 diabetic patients show a decreased diurnal serum melatonin level and an increased pancreatic melatonin-receptor status. J Pineal Res. 2006;40(2):135–43. [DOI] [PubMed] [Google Scholar]
- 67.Peschke E, Stumpf I, Bazwinsky I, Litvak L, Dralle H, Mühlbauer E. Melatonin and type 2 diabetes–a possible link? J Pineal Res. 2007;42(4):350–8. [DOI] [PubMed] [Google Scholar]
- 68.Febbraio MA, White P, Southgate RJ, Hiscock N. Melatonin attenuates oxidative-stress induced insulin resistance and lipid peroxidation in human primary muscle cells. Diabetes. 2005;54:A317. [Google Scholar]
- 69.Winiarska K, Fraczyk T, Malinska D, Drozak J, Bryla J. Melatonin attenuates diabetes-induced oxidative stress in rabbits. J Pineal Res. 2006;40(2):168–76. [DOI] [PubMed] [Google Scholar]
- 70.Sudnikovich EJ, Maksimchik YZ, Zabrodskaya SV, Kubyshin VL, Lapshina EA, Bryszewska M, et al. Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats. Eur J Pharmacol. 2007;569(3):180–7. [DOI] [PubMed] [Google Scholar]
- 71.Navarro-Alarcón M, Ruiz-Ojeda FJ, Blanca-Herrera RM, A-Serrano MM, Acuña-Castroviejo D, Fernández-Vázquez G, et al. Melatonin and metabolic regulation: a review. Food Funct. 2014;5(11):2806–32. [DOI] [PubMed] [Google Scholar]
- 72.Nishikawa T, Kukidome D, Sonoda K, Fujisawa K, Matsuhisa T, Motoshima H, et al. Impact of mitochondrial ROS production on diabetic vascular complications. Diabetes Res Clin Pract. 2007;77(3):S41–5. [DOI] [PubMed] [Google Scholar]
- 73.Bertuglia S, Reiter RJ. Melatonin reduces microvascular damage and insulin resistance in hamsters due to chronic intermittent hypoxia. J Pineal Res. 2009;46(3):307–13. [DOI] [PubMed] [Google Scholar]
- 74.Peschke E, Bähr I, Mühlbauer E. Melatonin and pancreatic islets: interrelationships between melatonin, insulin and glucagon. Int J Mol Sci. 2013;14(4):6981–7015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Shieh JM, Wu HT, Cheng KC, Cheng JT. Melatonin ameliorates high fat diet-induced diabetes and stimulates glycogen synthesis via a PKCζ‐Akt‐GSK3β pathway in hepatic cells. J Pineal Res. 2009;47(4):339–44. [DOI] [PubMed] [Google Scholar]
- 76.Venegas C, García JA, Doerrier C, Volt H, Escames G, López LC, et al. Analysis of the daily changes of melatonin receptors in the rat liver. J Pineal Res. 2013;54(3):313–21. [DOI] [PubMed] [Google Scholar]
- 77.Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, et al. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3‐kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res. 2006;41(1):67–72. [DOI] [PubMed] [Google Scholar]
- 78.Owino S, Sánchez-Bretaño A, Tchio C, Cecon E, Karamitri A, Dam J, et al. Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI 3K activity. J Pineal Res. 2018;64(3):e12462. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79.Sauer LA, Dauchy RT, Blask DE. Melatonin inhibits fatty acid transport in inguinal fat pads of hepatoma 7288CTC-bearing and normal Buffalo rats via receptor-mediated signal transduction. Life Sci. 2001;68(25):2835–44. [DOI] [PubMed] [Google Scholar]
- 80.Faria JA, Kinote A, Ignacio-Souza LM, de Araújo TM, Razolli DS, Doneda DL, et al. Melatonin acts through MT1/MT2 receptors to activate hypothalamic Akt and suppress hepatic gluconeogenesis in rats. Am J Physiol Endocrinol Metab. 2013;305(2):E230–42. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due confidential and private information but are available from the corresponding author on reasonable request.