Interaction of Melatonin and MTNR1B Genotype on Glucose Control - Study 1
Phase: NA
Conditions: Glucose, Circadian Rhythm, Melatonin, Genes
Sponsor: Brigham and Women's Hospital

 
 
 
 
 
 
 
Interaction of Melatonin and MTNR1B Genotype on 
Glucose Control - Study 1 
NCT02642640 
October 21, 2025 
 

Study Protocol 
Using a randomized, double-blind, placebo-controlled, cross-over design, we aim to determine 
the effects of 5 mg melatonin oral administration and its interaction with MTNR1B (encodes the 
high-affinity melatonin receptor 1B) genotypes on disposition index (DI), first-phase insulin release, 
insulin sensitivity, and glucose tolerance, using a high-frequency intravenous glucose tolerance 
test (IVGTT) performed in the afternoon. Both carriers of the MTNR1B risk SNP and non-carriers 
will be randomized to the order of conditions (melatonin/placebo) in a crossover design. The 
Internal Drug Services will follow a randomization scheme in which participants will be block-
randomized (block size equals 2) into two treatment orders (melatonin/placebo or 
placebo/melatonin). Men and women will be randomized equally between the melatonin and 
placebo groups. Participants undergo one 5-day in-laboratory stay, during which participants 
maintain their habitual sleep/wake cycle as they have been doing for the 2-3 weeks prior to each 
admission. Following each admission and after a baseline day and night, participants receive 5 
mg of melatonin or placebo during Wake Period (WP) 2, ~1h before the glucose infusion of IVGTT 
(ensuring peak levels at the start and high levels throughout the 3-h IVGTT). After two washout 
days and nights, on WP4, participants receive the opposite treatment to the one received on WP2. 
IVGTT’s begin ~1h after melatonin/placebo administrations, and a mixed meal test begin ~1h 
after IVGTT ends. This approach allows us to assess an unresolved question which is whether 
melatonin and its interaction with the MTNR1B risk variant have a more profound impact on 
peripheral insulin sensitivity or, by contrast, on pancreatic insulin secretion. Investigational Drug 
Services (IDS) block-randomize participants (block size 2) into two treatment orders 
(melatonin/placebo or placebo/melatonin). In addition to the research participants, all personnel 
who have contact with the participants or with the endpoint assessment are blinded (all 
investigators, recruitment personnel, technicians, nurses, and physicians).  
 
Statistical methods 
We apply mixed model analysis on outcomes deduced from FSIGT, with melatonin/placebo as 
fixed factor, and individual as random factor (DI, insulin sensitivity, beta-cell function). To test the 
interaction effect with MTNR1B genotype, we use the same model, but include genotype (carriers 
vs. non-carriers) as a second fixed factor. Although genotype groups be matched for sex, age, 
and BMI, we test whether any of these factors are significant covariates. We also test for any 
order effects. Outcome variables exhibiting non-normality will be transformed as appropriate.