MTNR1B SNP*Food Timing Interaction on Glucose Control (ONTIME-MT)

MTNR1B SNP*Food Timing Interaction on Glucose Control in a Late Eater Mediterranean Population

The purpose of this investigation is to assess the role of melatonin receptor 1B (MTNR1B) single nucleotide polymorphism (SNP)*food timing interaction on glucose control in the deleterious effect in a vulnerable population with regular exposure to concurrent high melatonin and food intake as late night eaters (those having dinner within 2.5 h before their usual bed time). With the results from this study, we expect to advance our understanding of the role of endogenous melatonin on glucose metabolism in late night eaters and carriers of the MTNR1B risk allele, with potential implications on the guidelines to mitigate risk of type 2 diabetes in late night eaters and carriers of the MTNR1B risk allele.

Study Overview

• Status: Completed
• Conditions: Non-Diabetic Disorder of Endocrine Pancreas
• Intervention / Treatment: Behavioral: Early OGTT; Behavioral: Late OGTT

Detailed Description

Late-night dinner eating is associated with increased risk for type-2-diabetes. The underlying mechanism is unclear. One explanatory hypothesis is that the concurrence of elevated circulating melatonin and high glucose concentrations (characterizing late-eating) leads to impaired glucose-tolerance. However, to date, no study has tested the influence of physiological melatonin concentrations on glucose tolerance. The discovery of melatonin receptor MTNR1B as a diabetes risk gene provides evidence for a role of physiological levels of melatonin in glucose control.

The aim of the current study is to test the hypothesis that the concurrence of meal timing with elevated endogenous melatonin concentrations results in impaired glucose control and that this effect is stronger in homozygous MTNR1B risk carriers than in non-carriers. To do so we will test glucose tolerance using identical mixed meals under two glucose oral tolerance test (OGTT) conditions: a) delayed OGTT or Late Eating (LE): starting1 hour before their usual bed time, b) advanced OGTT or Early Eating (EE): starting 4 hours before habitual bed time, in a randomized, cross-over study design.

These findings could support a clinical application for the screening of this SNP and the possibility of implementing tailored and cost-effective behavioral interventions to prevent type 2 diabetes in vulnerable populations.

These goals will be achieved through a specific approach:

• Interventional (randomized, cross-over controlled trials) (Aim 1): To study the potential interaction between meal timing (dinner) and genetic variants MTNR1B for glucose tolerance (n=1000).

• Study Type: Interventional
• Enrollment (Actual): 889
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Murcia, Spain, 30100
    • University of Murcia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Body Mass Index: > 18.5 o < 40 kg/m2
• Age: between 18 and 65 year of age
• European ancestry
• Day workers

Exclusion Criteria:

• Receiving treatment with thermogenic, lipogenic, or drugs
• Diabetes mellitus, chronic renal failure, hepatic diseases, or cancer diagnosis
• Bulimia diagnosis, prone to binge eating
• Undergoing treatment with Type 2 diabetes mellitus (high blood sugar) medications such as Metformin or other non-Metformin oral anti-diabetic drugs such as sulfonylureas, meglitinides, or glitazones
• Undergoing treatment with Corticosteroids/steroids, Growth hormone, Anticoagulant medicines, or blood thinners, Beta blockers for hypertension, Medications for sleep, Fluvoxamine, Opioids or Amphetamines, Tranquilizers, nonsteroidal anti-inflammatory drugs.
• Pregnant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early OGTT, then late OGTT in MTNR1B CC; Oral glucose tolerance test (OGTT) in homozygous non-carriers (CC) for MTNR1B rs10830963 in Early and Late conditions	Behavioral: Early OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under early condition (4 hours before habitual bedtime); Behavioral: Late OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under late condition (1 hour before habitual bedtime)
Experimental: Early OGTT, then late OGTT in MTNR1B CG; Oral glucose tolerance test (OGTT) in heterozygous (CG) risk allele carriers for MTNR1B rs10830963 in Early and Late conditions	Behavioral: Early OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under early condition (4 hours before habitual bedtime); Behavioral: Late OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under late condition (1 hour before habitual bedtime)
Experimental: Early OGTT, then late OGTT in MTNR1B GG; Oral glucose tolerance test (OGTT) in homozygous (GG) risk allele carriers for MTNR1B rs10830963 in Early and Late conditions	Behavioral: Early OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under early condition (4 hours before habitual bedtime); Behavioral: Late OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under late condition (1 hour before habitual bedtime)
Experimental: Late OGTT, then Early OGTT in MTNR1B CC; Oral glucose tolerance test (OGTT) in heterozygous (CG) risk allele carriers for MTNR1B rs10830963 in Early and Late conditions	Behavioral: Early OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under early condition (4 hours before habitual bedtime); Behavioral: Late OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under late condition (1 hour before habitual bedtime)
Experimental: Late OGTT, then Early OGTT in MTNR1B CG; Oral glucose tolerance test (OGTT) in heterozygous (CG) risk allele carriers for MTNR1B rs10830963 in Early and Late conditions	Behavioral: Early OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under early condition (4 hours before habitual bedtime); Behavioral: Late OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under late condition (1 hour before habitual bedtime)
Experimental: Late OGTT, then Early OGTT in MTNR1B GG; Oral glucose tolerance test (OGTT) in heterozygous (CG) risk allele carriers for MTNR1B rs10830963 in Early and Late conditions	Behavioral: Early OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under early condition (4 hours before habitual bedtime); Behavioral: Late OGTT; Oral glucose tolerance test using identical mixed 75 gr of glucose under late condition (1 hour before habitual bedtime)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) Glucose	Glucose levels are measured along 120 minutes corresponding to at early and late condition in each visit. The Area Under the Curve was calculated as the sum of the area of several trapezoids. This trapezoids was obtained at times 0-30 min, 30-60 min, 60-90 min, 90-120 min. The values are the difference between the late and the early condition.	Along 120 minutes in visits 1 and 2
Disposition Index (DI)	Disposition Index (DI) is the product of insulin sensitivity times by the amount of insulin secreted in response to blood glucose levels. Disposition index is used as a measure of beta cell function and the ability of the body to dispose of a glucose load. This index was determined by this formula: DI= CIR × ISI, where CIR is the measure Corrected Insulin Response, and ISI is Insulin Sensitivity Index. The values are the difference between the late and the early condition. Higher DI indicates an increased beta cell function and increased ability of the body to dispose of a glucose load.	Along 120 minutes in visits 1 and 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corrected Insulin Response (CIR)	The measure of Corrected Insulin Response (CIR) uses the insulin and glucose levels at minute 30, integrating these values in the formula: CIR= l30/(G30 × (G30 - 70)).The values are the difference between the late and the early conditions. CIR is an index that assesses the insulin secretion capacity of B cells. A low CIR implies hyposecretion in response to glucose levels.	At minute 30 during the visit 1 and 2.
Insulin Sensitivity Index (ISI)	Insulin Sensitivity Index is a measurement which integrates fasting glucose and insulin concentrations (0 min) and the mean of the glucose and insulin levels from 0 to 120 minutes (0, 30, 60, 90 and 120 min), from an OGTT, to measure insulin sensitivity. This formula allows its use in clinical settings as well as in large epidemiological studies. The values are the difference between the late and the early condition. Elevated ISI values typically indicate a favorable outcome. This index reflects the body's responsiveness to insulin, a hormone crucial for regulating blood sugar levels. Higher sensitivity to insulin suggests that cells efficiently utilize insulin's signals, promoting better blood sugar management. Lower ISI may lead to challenges in maintaining stable blood glucose levels and is often associated with conditions such as type 2 diabetes and metabolic syndrome.	Along 120min in visits 1 and 2
Fasting Glucose	Fasting glucose (or basal glucose) is a simple measurement of glucose concentrations at minute 0 to see how glucose levels rise immediately after an OGTT. The values are the difference between the late and the early condition.	At minute 0 in visit 1 and 2.
Fasting Insulin	Fasting insulin (or basal insulin) is a simple measurement of insulin concentrations at minute 0 to see how insulin levels rise immediately after an OGTT.The values are the difference between the late and the early condition.	At minute 0 in visit 1 and 2
Serum Melatonin	Measurement of serum melatonin is made at time 0 and at time 120 in both the early and late conditions of everyone.	At baseline and 120 minutes in visit 1 and 2
Dim Light Melatonin Onset (DLMO) at Early Condition Only	This measurement shows the decimal time of the onset of melatonin in dim light conditions. In the case of DLMO, we only performed this measure at the early condition in order to get the analysis of melatonin during 5 hours (4 hours before the habitual bedtime and 1 hour later), as it is described in literature (DOI: 10.1002/oby.23749).	Melatonin measured every half hour for 5 hours at Early condition in all participants

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Temperature Record (Mean Value 10hours Daytime)	Measured using a temperature sensor which records the temperature during 7 days. We only determined it during the washout period (neither early nor late conditions).	For 1 week between visit 1 and 2
Activity Record (Mean Value 10hours Daytime)	During the seven days of the study, individuals wore a wristwatch in their non-dominant hand, that integrates two sensors: a temperature sensor, and an accelerometer sensor that records physical activity and body position data (G Acceleration Data Logger UA-004-64; Onset Computer, Bourne, MA, USA). Activity was expressed as the change in degrees per minute (Δ°/min). We calculated the average activity value during the 10 consecutive hours of maximum values. We only determined it during the washout period (neither early nor late conditions).	For 1 week between visit 1 and 2
Light Exposure (Mean Value 10hours Daytime)	Measured using a light sensor during 7 days. We only determined it during the washout period (neither early nor late conditions).	For 1 week between the visits 1 and 2
Sleep Duration	Sleep duration will be computed from self-reported. We only determined it during the washout period (neither early nor late conditions).	For 1 week between visit 1 and 2
Total Energy Intake	Total energy intake in kcal/day will be computed with a 7-day dietary log. We only determined it during the washout period (neither early nor late conditions).	For 1 week between visit 1 and 2
Dietary Composition	Macronutrient and micronutrient intake will be computed from 7-days of self-reported 24-hr dietary recalls. Percentage Kcal respect to the Total Energy Intake. We only determined it during the washout period (neither early nor late conditions).	For 1 week between visit 1 and 2
Dietary Intake Timing	Food timing will be self-reported and averaged across 7-days of 24-hour dietary recalls. We only determined it during the washout period (neither early nor late conditions).	For 1 week between visit 1 and 2
Physical Activity	Assessed using the International Physical Activity Questionnaire (IPAQ). This international questionnaire measures physical activity through the amount of energy expended carrying out physical activity i.e., Metabolic Units (MET) minutes a week. The higher the MET, the more amount of physical activity the individual performs. This allows us to classify low, moderate, or vigorous activity. 7 or more days of any combination of walking, moderate-intensity or vigorous intensity activities achieving a minimum of at least 3000 MET minutes a week. We only determined it during the washout period (neither early nor late conditions). Formula for computation of Met-minutes: Walking MET-minutes/week = 3.3 * walking minutes * walking "days"; Moderate MET-minutes/week = 4.0 * moderate-intensity activity minutes * moderate days; Vigorous MET-minutes/week = 8.0 * vigorous-intensity activity minutes * vigorous-intensity days	During the week of washout
Chronotype	Assessed using the Morningness-Eveningness Questionnaire (MEQ). Its main purpose is to measure whether a person's circadian rhythm produces peak alertness in the morning, in the evening, or in between. It is a score that indicates the degree to which the individual favors the morning over the night. We only determined it during the washout period (neither early nor late conditions). Values: Min: 17 Max: 86 Explanation: 17-30: extreme eveningness 31-41: eveningness 42-58: neither 59-69: morningness 70-86: extreme morningness	During the week of washout
Emotional Eating	Assessed using the Emotional Eating Questionnaire (EEQ). This questionnaire classifies individuals based on the relationship between food intake and emotions. Score between 0 and 30. We only determined it during the washout period (neither early nor late conditions). Explanation: 0-5: nothing emotional 5-10: less emotional 10-20: emotional 20-30: Very emotional	During the week of washout
Sleep Quality	Assessed using the Pittsburgh Sleep Quality Index (PSQI). This questionnaire is used to quantitatively assess the quality of sleep. 7 scores are obtained that inform us about various aspects of sleep quality. We only determined it during the washout period (neither early nor late conditions). Score between 0 and 21. Total score of the questionnaire is divided into 7 items. Those items have a score from 0 (no problem) to 3 (severe problem). 0-5: sleep quality optimum 6-21: sleep disorders	During the week of washout
Insomnia	Assessed using the Insomnia Severity Index (ISI). This questionnaire has 5 items and is used to assess the possible existence of sleep problems. According to the score obtained, a classification is made from no insomnia to severe clinical insomnia. We only determined it during the washout period (neither early nor late conditions). Score ranges between 0 and 28 Explanation: 0-7: no insomnia 8-14: subclinical insomnia 15-21: moderate insomnia 22-28: severe insomnia The higher the score, the more harmful	During the week of washout
Depression	Assessed using the Patient Health Questionnaire (PHQ-9). This instrument aims to help the diagnosis of depression through the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), and to determine the severity of the disorder. It is made up of 9 items that refer to the last two weeks. The score ranges between 0 and 27. We only determined it during the washout period (neither early nor late conditions). 0-4: no depression 5-9: mild depression 10-14: moderate depression 15-19: moderate-severe depression 20-27: severe depression Explanation: 0-4: no depression 5-9: mild depression 10-14: moderate depression 15-19: moderate-severe depression 20-27: severe depression The higher the score, the more harmful	During the week of washout

Collaborators and Investigators

• Sponsor: Universidad de Murcia
• Investigators: Study Chair: Purificación Gomez Abellan, PHD, Universidad de Murcia

Publications and helpful links

General Publications

• Garaulet M, Lopez-Minguez J, Dashti HS, Vetter C, Hernandez-Martinez AM, Perez-Ayala M, Baraza JC, Wang W, Florez JC, Scheer FAJL, Saxena R. Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial. Diabetes Care. 2022 Mar 1;45(3):512-519. doi: 10.2337/dc21-1314.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2017
• Primary Completion (Actual): March 13, 2020
• Study Completion (Actual): March 13, 2020

Study Registration Dates

• First Submitted: January 26, 2017
• First Submitted That Met QC Criteria: January 26, 2017
• First Posted (Estimated): January 30, 2017

Study Record Updates

• Last Update Posted (Actual): April 16, 2025
• Last Update Submitted That Met QC Criteria: March 27, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Glucose tolerance test, MTNR1B, nutrigenomics, food timing
• Other Study ID Numbers: 2017ES00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No