Metabolic Effects of Melatonin Treatment

Sponsor

University of Aarhus (Other)

Overall Status

Completed

CT.gov ID

NCT03859934

Collaborator

University of Copenhagen (Other)

Enrollment

Location

Arms

22.7

Actual Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Modern living is associated with an epidemic of type 2 diabetes mellitus (T2DM). Sleep disturbances such as insomnia or frequent awakenings are strong risk factors for T2DM with several studies indicating a central role of melatonin. Additionally, a certain single nucleotide polymorphism in the melatonin receptor gene, MTNR1B rs10830963, with an allele frequency of 30 %, is associated with increased fasting plasma glucose and T2DM. Due to treatment of, among other things, insomnia, the use of melatonin is increasing rapidly in Denmark with a 100-fold increase from 2007-2012 in children and adolescents. No previous studies have thoroughly assessed changes in glucose and fatty acid metabolism after 3 months of melatonin treatment in patients with T2DM.

Condition or Disease	Intervention/Treatment	Phase
Metabolic Disease Insulin Sensitivity Glucose Metabolism Disorders (Including Diabetes Mellitus) Type 2 Diabetes Mellitus Blood Pressure Inflammation	Drug: Melatonin Drug: Placebo Oral Tablet	Phase 1

Detailed Description

Main research questions:

Does chronic melatonin treatment change insulin secretion in T2DM patients?
Does chronic melatonin treatment change insulin sensitivity in T2DM patients?
Does the MTNR1B rs10830963 risk allele alter the insulin secretion and insulin sensitivity compared with carries of the normal variant after chronic melatonin treatment?
Does chronic melatonin treatment change insulin signalling in muscle - and adipose tissue? Design: A randomized, double-blinded, placebo controlled, crossover study, including 18 participants with T2DM. We aim to recruit 9 homozygous carriers of the normal allele and 9 hetero - or homozygous for the risk allele.

Participants will be examined on two occasions, 1) after 3 months of daily melatonin treatment before bedtime (10 mg), and 2) after 3 months of daily placebo treatment before bedtime.

On the study days, participants will initially undergo a basal period with glucose - and palmitate tracer infusions to assess endogenous glucose production and free fatty acid production. Afterwards a Botnia clamp, which combines an intravenous glucose tolerance test and a hyperinsulinemic euglycemic clamp, will be performed to assess β-cell function and insulin sensitivity. On both study days muscle - and fat biopsies will be performed under both basal and hyperinsulinemic euglycemic conditions.

Perspectives: It is highly relevant to evaluate the chronic effects of melatonin on glucose - and fat metabolism given the increase in melatonin consumption. Furthermore, the study may open for new treatment options of T2DM if beneficial effects of oral melatonin are detected.

Study Design

Study Type:

Interventional

Actual Enrollment :

17 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Randomized, placebo controlled, double blinded crossover studyRandomized, placebo controlled, double blinded crossover study

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Metabolic Effects of Melatonin Treatment

Actual Study Start Date :

Sep 26, 2019

Actual Primary Completion Date :

May 3, 2021

Actual Study Completion Date :

Aug 18, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Melatonin 10 mg melatonin each day 1 hour before bedtime for 3 months	Drug: Melatonin Melatonin treatment Other Names: Melatonin treatment
Placebo Comparator: Placebo Placebo each day 1 hour before bedtime for 3 months	Drug: Placebo Oral Tablet Placebo treatment Other Names: Placebo treatment

Arm

Intervention/Treatment

Active Comparator: Melatonin

10 mg melatonin each day 1 hour before bedtime for 3 months

Drug: Melatonin

Melatonin treatment

Other Names:

Melatonin treatment

Placebo Comparator: Placebo

Placebo each day 1 hour before bedtime for 3 months

Drug: Placebo Oral Tablet

Placebo treatment

Other Names:

Placebo treatment

Outcome Measures

Primary Outcome Measures

Change of insulin sensitivity [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment and compared afterwards with a paired T-tes]
Insulin sensitivity is assessed by a hyperinsulinemic euglycemic clamp, unit: mg/kg/min (mg of glucose to maintain euglycemia per kilogram of weight per minuts)
Change of insulin secretion change [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Insulin secretion is assessed by an intravenous glucose tolerance test, unit: pmol/L (insulin)
MTNR1a rs10830963 influence on change in insulin sensitivity and insulin secretion [The outcome will be measured after 3 months of placebo treatment and again after 3 months of melatonin treatment]
MTNR1a rs10830963 genotype influence on insulin sensitivity and insulin secretion (see outcome 1 + 2)
Change of insulin signalling [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Insulin signalling in muscle and adipose tissue assessed by western blot

Secondary Outcome Measures

Change of ambulatory blood pressure [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Ambulatory blood pressure assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (Unit: mmHg)
Change of arterial stiffness [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Arterial stiffness assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (unit: m/s)
Change of gut microbiome [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Feces analysis of microbial mRNA
Change of sleep evaluation 1 [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Pittsburg Sleep Quality Index Questionnaire (Points on a scale: range 0-57)
Change of sleep evaluation 2 [After 3 months treatmentThe outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Epworth Sleepiness Scale Questionnaire (Points on a scale: range 0-24)
Change of psychological health 1 [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Major Depression Inventory Questionnaires (points on a scale: range 0-65)
Change of psychological health 2 [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
World Health Organization 5 Questionnaires (points on a scale: range 0-25)
Hormonal changes [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Ghrelin, HbA1c, GLP-1, GLP-2, GIP, free fatty acids (FFA), leptin, cytokines, adiponectin, growth hormone, cortisol, hsCRP, CD163, MBL, IGF-1 and proinsulin measured by ELISA, RIA, or routine biochemical analysis. Unit: pmol/L
Change of glucose and palmitate kinetics [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Tracer technique with infusion of radioactive labeled glucose and palmitate for determination of rate of appereance. Unit: mikromol/min
Change of regional glucose and palmitate uptake [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Forearm model with arteriovenous differences of glucose and palmitate (Arterial glucose minus venous glucose = forearm uptake (unit mmol/l). The same applies for palmitate
Change of DEXA-scans [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Evaluation of body composition and bone mineral density by DEXA-scan
Change of assessment of respiratory quotient (RQ) [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Assessment of respiratory quotient (RQ) with indirect calorimetry (unit: VCO2/VO2)
Change of assessment of resting energy expenditure (REE) [The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment]
Assessment of resting energy expenditure (REE) with indirect calorimetry (Unit J/s)

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 70 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Male sex
Caucasian race
Type 2 Diabetes Mellitus (T2DM)
T2DM duration of maximum 20 years
Age 40-70 years
BMI between 25-35 kg/m2 at T2DM debut
Written consent prior to study participation

Exclusion Criteria:

3 daily antihypertensive drugs
Blood pressure > 160/100 mmHg
Insulin treatment
3 daily oral antidiabetic drugs
1 lipid lowering drug
HbA1c > 65
Heart failure (New York Heart Association Class III or IV), liver disease (alanine aminotransferase (ALAT) > twice the upper limit of normal serum concentration), plasma creatinine > 130 µmol/L and/or albuminuria, goiter, active cancer, acute or chronic pancreatitis
Treatment with antidiabetic medicine that cannot be paused on study days (or for a week if the participants is treated with longtime-acting GLP-1 analogs)
Shift work within the last year
Travel across >4 time zones planned within the next 6 months
Use of melatonin on a regular basis within the last year
Severe illness
14 units of alcohol/week
Previous diagnosis of a sleep disorder
Present or earlier alcohol or drug abuse
Unable to give informed consent
Allergy towards melatonin
Daily consumption of benzodiazepines, fluvoxamine, amiodarone, efavirenz, fluoroquinolones, rifampicin, and carbamazepine due to interactions with the pharmacokinetics of melatonin.
Severe sleep apnea (>30 respiration breaks/hour over 10 seconds)
Medical treated depression or anxiety disorders within the last 3 years
Daily consumption of selective serotonin reuptake inhibitors or tricyclic antidepressants

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Research Laboratory	Aarhus		Denmark	8200

Sponsors and Collaborators

University of Aarhus
University of Copenhagen

Investigators

Principal Investigator: Esben Stistrup Lauritzen, MD, Medical Research Laboratory
Principal Investigator: Ulla Kampmann Opstrup, MD, PhD, Aarhus University Hospital
Principal Investigator: Julie Støy, MD, PhD, Aarhus University Hospital