MTNR1B SNP*Food Timing Interaction on Glucose Control

Study Overview
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Brief Summary
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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.

Detailed Description
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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 in obese women (n=1000).

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

Conditions
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Non-Diabetic Disorder of Endocrine Pancreas

Intervention / Treatment
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* Behavioral: Early OGTT
* Behavioral: Late OGTT


Participation Criteria
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Eligibility Criteria
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IInclusion Criteria: Body Mass Index: > 18.5 o < 40 kg/m2 Age: between 18 and 65 year of age Caucasian 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) glucose | Investigators will measure insulin and glucose levels for 120 minutes at day time and night time visits, and compare them by genotype at selected loci. | between 0-120 minutes, Visit 2 and 3 | 
| Disposition index | Disposition index will be determined by frequently sampled oral glucose tolerance test | between 0-120 minutes, Visit 2 and 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Corrected Insulin Response | Corrected Insulin Response | between 0-120 minutes, Visit 2 and 3 | 
| Insulin Sensitivity Index | Insulin Sensitivity Index | between 0-120 minutes, Visit 2 and 3 | 
| Fasting glucose | Fasting glucose | between 0-120 minutes, Visit 2 and 3 | 
| Fasting insulin | Fasting insulin | 0-120 minutes, Visit 2 and 3 | 
| Serum Melatonin | Serum Melatonin | at baseline and 120 minutes, Visit 2 and 3 | 
| DLMO | Dim Light Melatonin Onset | between 0-5 hours, Visit 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucose tolerance test, MTNR1B, nutrigenomics, food timing