Effects of Melatonin on Glycemic Variability in Type 2 Diabetes Mellitus: Protocol for a Crossover, Double-Blind, Placebo-Controlled Trial

Abstract

Background: Glycemic variability is recognized as a significant factor contributing to the development of micro- and macrovascular complications in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have shown that melatonin, a hormone involved in regulating various biological rhythms, including those related to glucose regulation, such as hunger, satiety, sleep, and circadian hormone secretion (ie, cortisol, growth hormone, catecholamines, and insulin), is deficient in individuals with T2DM. This raises an important question: Could melatonin replacement potentially reduce glycemic variability in these patients? This warrants investigation as a novel approach to improving glycemic control and reducing the risk of complications associated with T2DM.

Objective: We aimed to investigate whether melatonin replacement in individuals with T2DM who supposedly have melatonin deficiency can positively impact the regulation of insulin secretion rhythms and improve insulin sensitivity, ultimately resulting in a reduction in glycemic variability.

Methods: This study will use a crossover, randomized, double-blind, placebo-controlled trial design. Patients with T2DM in group 1 will receive 3 mg of melatonin at 9:00 PM in the first week, undergo a washout period in the second week, and receive a placebo in the third week (melatonin-washout-placebo). Group 2 will be randomized to receive a placebo-washout-melatonin sequence (3 mg). Capillary blood glucose levels will be measured at 6 different times before and after meals during the last 3 days of the first and third weeks. The study aims to compare the mean differences in blood glucose levels and the coefficient of glycemic variability in patients receiving melatonin and placebo during the first and third weeks. After analyzing the initial results, the number of needed patients will be recalculated. If the recalculated number is higher than 30, new participants will be recruited. Thirty patients with T2DM will be randomized into the 2 groups: melatonin-washout-placebo or placebo-washout-melatonin.

Results: Participant recruitment took place between March 2023 to April 2023. In all, 30 participants were eligible and completed the study. We expect that patients will show different glycemic variability on the days they receive placebo or melatonin. Studies on melatonin and glycemic control have shown both positive and negative results. We hope that there will be a positive outcome regarding glycemic variability (ie, a reduction in glycemic variability), as melatonin has a well-described chronobiotic effect in the literature.

Conclusions: This study aims to determine whether melatonin supplementation can effectively reduce glycemic variability in patients with T2DM. The crossover design is necessary due to the multiple variables involved in the circadian variations of glucose, including diet, physical activity, sleep parameters, and pharmacological treatments. The relatively low cost of melatonin and its potential role in reducing the severe complications associated with T2DM have motivated this research effort. Furthermore, the indiscriminate use of melatonin in current times makes conducting this study essential to evaluate the effect of this substance in patients with T2DM.

Trial registration: Brazilian Registry of Clinical Trials RBR-6wg54rb; https://ensaiosclinicos.gov.br/rg/RBR-6wg54rb.

International registered report identifier (irrid): DERR1-10.2196/47887.

Keywords: T2DM; circadian rhythm; cross-over studies; glucose; glycemic control; glycemic variability; melatonin; randomized controlled trial; type 2 diabetes mellitus.

Figure 1

Flowchart.

Figure 2

Sample table showing how results will be reported. Unpaired-sample t tests or Wilcoxon tests will be used.