Metabolic Effects of Melatonin Treatment
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 17
- 试验地点
- 1
- 主要终点
- Change of insulin sensitivity
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 40 Years 至 70 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •> 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
研究组 & 干预措施
Melatonin
10 mg melatonin each day 1 hour before bedtime for 3 months
干预措施: Melatonin (Drug)
Placebo
Placebo each day 1 hour before bedtime for 3 months
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Change of insulin sensitivity
时间窗: 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)
Change of insulin secretion change
时间窗: 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)
Change of insulin signalling
时间窗: 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
MTNR1a rs10830963 influence on change in insulin sensitivity and insulin secretion
时间窗: 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)
次要结局
- Change of glucose and palmitate kinetics(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(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)
- Change of DEXA-scans(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)(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)(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)
- Change of ambulatory blood pressure(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)
- Change of arterial stiffness(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)
- Change of gut microbiome(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)
- Change of sleep evaluation 1(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)
- Change of sleep evaluation 2(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(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)
- Change of psychological health 2(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)
- Hormonal changes(The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment)