Metabolic Effects of Melatonin Treatment

NCT ID: NCT03859934

Last Updated: 2021-08-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-26
• Study Completion Date: 2021-08-18

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.

Detailed Description

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.

Main research questions:

1. Does chronic melatonin treatment change insulin secretion in T2DM patients?

2. Does chronic melatonin treatment change insulin sensitivity in T2DM patients?

3. Does the MTNR1B rs10830963 risk allele alter the insulin secretion and insulin sensitivity compared with carries of the normal variant after chronic melatonin treatment?

4. 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.

Conditions

Metabolic Disease; Insulin Sensitivity; Glucose Metabolism Disorders (Including Diabetes Mellitus); Type 2 Diabetes Mellitus; Blood Pressure; Inflammation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Melatonin

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

Group Type: ACTIVE_COMPARATOR

Melatonin

Intervention Type: DRUG

Melatonin treatment

Placebo

Placebo each day 1 hour before bedtime for 3 months

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

Placebo treatment

Interventions

Melatonin

Melatonin treatment

Intervention Type: DRUG

Placebo Oral Tablet

Placebo treatment

Intervention Type: DRUG

Other Intervention Names

Melatonin treatment; Placebo treatment

Eligibility Criteria

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

• Minimum Eligible Age: 40 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

University of Copenhagen

OTHER

Sponsor Role: collaborator

University of Aarhus

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Esben Stistrup Lauritzen, MD

Role: PRINCIPAL_INVESTIGATOR

Medical Research Laboratory

Ulla Kampmann Opstrup, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Aarhus University Hospital

Julie Støy, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Aarhus University Hospital

Locations

Medical Research Laboratory

Aarhus, , Denmark

Countries

Denmark

Other Identifiers

2019-000213-37

Identifier Type: -

Identifier Source: org_study_id