Metabolic Effects of Melatonin Treatment

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:

• 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.

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