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Metabolic Effects of Melatonin Treatment

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ClinicalTrials.gov Identifier: NCT03859934
Recruitment Status : Recruiting
First Posted : March 1, 2019
Last Update Posted : September 30, 2019
Sponsor:
Collaborator:
University of Copenhagen
Information provided by (Responsible Party):
University of Aarhus

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:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Randomized, placebo controlled, double blinded crossover study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Metabolic Effects of Melatonin Treatment
Actual Study Start Date : September 26, 2019
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : September 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Melatonin

Arm Intervention/treatment
Active Comparator: Melatonin
10 mg melatonin each day 1 hour before bedtime for 3 months
Drug: Melatonin
Melatonin treatment
Other Name: Melatonin treatment

Placebo Comparator: Placebo
Placebo each day 1 hour before bedtime for 3 months
Drug: Placebo Oral Tablet
Placebo treatment
Other Name: Placebo treatment




Primary Outcome Measures :
  1. Change of insulin sensitivity [ Time Frame: 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)

  2. Change of insulin secretion change [ Time Frame: 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)

  3. MTNR1a rs10830963 influence on change in insulin sensitivity and insulin secretion [ Time Frame: 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)

  4. Change of insulin signalling [ Time Frame: 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 :
  1. Change of ambulatory blood pressure [ Time Frame: 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)

  2. Change of arterial stiffness [ Time Frame: 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)

  3. Change of gut microbiome [ Time Frame: The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment ]
    Feces analysis of microbial mRNA

  4. Change of sleep evaluation 1 [ Time Frame: 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)

  5. Change of sleep evaluation 2 [ Time Frame: 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)

  6. Change of psychological health 1 [ Time Frame: 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)

  7. Change of psychological health 2 [ Time Frame: 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)

  8. Hormonal changes [ Time Frame: 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

  9. Change of glucose and palmitate kinetics [ Time Frame: 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

  10. Change of regional glucose and palmitate uptake [ Time Frame: 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

  11. Change of DEXA-scans [ Time Frame: 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

  12. Change of assessment of respiratory quotient (RQ) [ Time Frame: 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)

  13. Change of assessment of resting energy expenditure (REE) [ Time Frame: 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03859934


Contacts
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Contact: Esben Stistrup Lauritzen, MD +4523608465 esben.lauritzen@clin.au.dk

Locations
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Denmark
Medical Research Laboratory Recruiting
Aarhus, Denmark, 8200
Contact: Esben S Lauritzen, M.D.    23608465    esben.lauritzen@clin.au.dk   
Sponsors and Collaborators
University of Aarhus
University of Copenhagen
Investigators
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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
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Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT03859934    
Other Study ID Numbers: 2019-000213-37
First Posted: March 1, 2019    Key Record Dates
Last Update Posted: September 30, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Insulin Resistance
Metabolic Diseases
Glucose Metabolism Disorders
Inflammation
Endocrine System Diseases
Pathologic Processes
Hyperinsulinism
Melatonin
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Central Nervous System Depressants