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.

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.

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

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)

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

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

MTNR1a rs10830963 genotype influence on insulin sensitivity and insulin secretion (see outcome 1 + 2)

The outcome will be measured after 3 months of placebo treatment and again after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

After 3 months treatmentThe outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

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

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

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

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

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