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| Name | Class |
|---|---|
| University of Copenhagen | OTHER |
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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:
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Melatonin | Active Comparator | 10 mg melatonin each day 1 hour before bedtime for 3 months |
|
| Placebo | Placebo Comparator | Placebo each day 1 hour before bedtime for 3 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Melatonin | Drug | Melatonin treatment |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Change of insulin sensitivity | 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 |
| Change of insulin secretion change | Insulin secretion is assessed by an intravenous glucose tolerance test, unit: pmol/L (insulin) | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| MTNR1a rs10830963 influence on change in insulin sensitivity and insulin secretion | 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 |
| Change of insulin signalling | Insulin signalling in muscle and adipose tissue assessed by western blot | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Change of ambulatory blood pressure | Ambulatory blood pressure assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (Unit: mmHg) | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Change of arterial stiffness |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Medical Research Laboratory | Aarhus | 8200 | Denmark |
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| ID | Term |
|---|---|
| D008659 | Metabolic Diseases |
| D007333 | Insulin Resistance |
| D044882 | Glucose Metabolism Disorders |
| D003924 | Diabetes Mellitus, Type 2 |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D009750 | Nutritional and Metabolic Diseases |
| D006946 | Hyperinsulinism |
| D003920 | Diabetes Mellitus |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D008550 | Melatonin |
| ID | Term |
|---|---|
| D014363 | Tryptamines |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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Randomized, placebo controlled, double blinded crossover study
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| Placebo Oral Tablet | Drug | Placebo treatment |
|
|
Arterial stiffness assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (unit: m/s) |
| The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Change of gut microbiome | Feces analysis of microbial mRNA | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Change of sleep evaluation 1 | Pittsburg Sleep Quality Index Questionnaire (Points on a scale: range 0-57) | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Change of sleep evaluation 2 | Epworth Sleepiness Scale Questionnaire (Points on a scale: range 0-24) | After 3 months treatmentThe outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Change of psychological health 1 | Major Depression Inventory Questionnaires (points on a scale: range 0-65) | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Change of psychological health 2 | World Health Organization 5 Questionnaires (points on a scale: range 0-25) | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Hormonal changes | 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 |
| Change of glucose and palmitate kinetics | 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 |
| Change of regional glucose and palmitate uptake | 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 |
| Change of DEXA-scans | Evaluation of body composition and bone mineral density by DEXA-scan | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Change of assessment of respiratory quotient (RQ) | Assessment of respiratory quotient (RQ) with indirect calorimetry (unit: VCO2/VO2) | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| Change of assessment of resting energy expenditure (REE) | Assessment of resting energy expenditure (REE) with indirect calorimetry (Unit J/s) | The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006571 | Heterocyclic Compounds |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |