MTNR1B SNP*Food Timing Interaction on Glucose Control

Not Applicable

Completed

Conditions: Non-Diabetic Disorder of Endocrine Pancreas

Interventions: Behavioral: Early OGTT
Behavioral: Late OGTT

Registration Number: NCT03036592

Lead Sponsor: Universidad de Murcia

Brief Summary: 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: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 889

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
MTNR1B CC	Early OGTT	Test glucose tolerance in homozygous non-carriers (CC) for MTNR1B rs10830963 in Early OGTT and Late OGTT
MTNR1B GG	Early OGTT	Test glucose tolerance in homozygous (GG) risk allele carriers for MTNR1B rs10830963 in Early OGTT and Late OGTT
MTNR1B GG	Late OGTT	Test glucose tolerance in homozygous (GG) risk allele carriers for MTNR1B rs10830963 in Early OGTT and Late OGTT
MTNR1B CC	Late OGTT	Test glucose tolerance in homozygous non-carriers (CC) for MTNR1B rs10830963 in Early OGTT and Late OGTT
MTNR1B CG	Late OGTT	Test glucose tolerance in heterozygous (CG) risk allele carriers for MTNR1B rs10830963 in Early OGTT and Late OGTT
MTNR1B CG	Early OGTT	Test glucose tolerance in heterozygous (CG) risk allele carriers for MTNR1B rs10830963 in Early OGTT and Late OGTT

Primary Outcome Measures

Name	Time	Method
Area Under the Curve (AUC) Glucose	Along 120 minutes in visits 1 and 2	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.
Disposition Index (DI)	Along 120 minutes in visits 1 and 2	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.

Secondary Outcome Measures

Name	Time	Method
Fasting Glucose	At minute 0 in visit 1 and 2.	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.
Serum Melatonin	At baseline and 120 minutes in visit 1 and 2	Measurement of serum melatonin is made at time 0 and at time 120 in both the early and late conditions of everyone.
Corrected Insulin Response (CIR)	At minute 30 during the visit 1 and 2.	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.
Fasting Insulin	At minute 0 in visit 1 and 2	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.
Dim Light Melatonin Onset (DLMO) at Early Condition Only	Melatonin measured every half hour for 5 hours at Early condition in all participants	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).
Insulin Sensitivity Index (ISI)	Along 120min in visits 1 and 2	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.