Bromocriptine and Insulin Sensitivity
Condition: Insulin Sensitivity
MeSH terms: Insulin Resistance; Hypersensitivity
Study type: Interventional

Summary: 
      In this study the investigators will examine the effect of dopamine (bromocriptine) on
      insulin sensitivity in lean and obese subjects. Furthermore, the investigators will examine
      whether the timing of bromocriptine administration has influence on insulin sensitivity.

      To do so, the investigators will include lean and obese subjects who will use 2 times 2 weeks
      bromocriptine. In randomized order, they will use it in the morning or in the evening.

      The investigators will examine insulin sensitivity by performing a 7-point oral glucose
      tolerance test.

      Furthermore, the investigators will examine energy expenditure and subjects will keep track
      of their eating behaviour in the 3 days before each study visit.
    

Detailed description: 
      Bromocriptine, a dopamine 2 receptor agonist, has recently been approved in the treatment of
      type 2 diabetes mellitus(DM2). Bromocriptine causes a significant improvement of fasting
      plasma glucose and Hba1C values. The exact mechanism of action of bromocriptine is still
      unknown.

      Earlier, the investigators performed a study to show the effects of bromocriptine on brown
      adipose tissue (BAT) activity (the DEBAT study (Medisch Etische Toetsingscommissie) METC nr
      2013_107). Namely, BAT, known for its capacity to dissipate excess energy, might have been
      involved in this process as stimulation by the sympathetic nervous system is the principal
      driving force in controlling BAT activity. However, the investigators have shown that
      bromocriptine did not influence BAT activity or energy expenditure in healthy, lean subjects.

      The investigators did found an effect of bromocriptine on insulin sensitivity unexpectedly,
      subjects became significantly less insulin sensitive after bromocriptine use.

      Circadian neuroendocrine rhythms, especially the dopaminergic and serotonergic
      neurotransmitter activity, play a pivotal role in the development of seasonal and
      non-seasonal changes in body fat stores and insulin sensitivity. Therefore, the timing of
      bromocriptine administration might be of great importance in changes in insulin sensitivity.
      Indeed, in the treatment for DM2, a bromocriptine quick release variant is given in the
      morning. In the former study the investigators instructed the subjects to use the
      bromocriptine in the evening in combination with the evening meal. The investigators decided
      to do so because bromocriptine had to be taken in combination with food. The investigators
      wanted a high level of dopamine just before the 18F-Fludeoxyglucose(18F-FDG) positron
      emission tomography (PET) computed tomography (CT) scan to get a maximum effect of dopamine
      on BAT. But the subjects had to be fasted for the OGTT and 18F-FDG-PET-CT scan. Therefore,
      the investigators decided to give the (long-acting) bromocriptine in the evening.

      Also, the effect of bromocriptine might be different in lean or obese subjects. Obesity is
      associated with an increased sympathetic tonus. Therefore, the baseline condition is
      different in lean or obese subjects which may cause different effects of bromocriptine
      treatment.

      In this study the investigators aim to investigate whether the timing (e.g. morning or
      evening) of bromocriptine administration (1,25mg/day during the first week and 2,50mg/day
      during the second week) has different effects on insulin sensitivity in both lean and obese
      males.

      At visit 1: Informed consent, medical history, vital signs and laboratory measurements will
      be obtained. The investigators will also perform an oral glucose tolerance test (OGTT), and
      an energy expenditure(EE) measurement after 60 minutes bed rest.

      After visit 1: subjects will start using bromocriptine (1,25mg/day during the first week and
      2,50mg/day during the second week) randomization to timing: in the morning or evening.

      Visit 2: EE after 60 minutes rest. OGTT. 2 weeks washout period Visit 3: EE after 60 minutes
      rest. OGTT. After visit 3: start using bromocriptine (1,25mg/day during the first week and
      2,50mg/day during the second week) at other time point.

      Visit 4: EE after 60 minutes rest. OGTT.
    

Intervention name(s): Bromocriptine
Intervention type(s): Drug
Intervention description(s): Investigating the randomized order for timing of bromocriptine administration
Other intervention name(s): Parlodel
Intervention MeSH terms: Bromocriptine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Keywords: Insulin Sensitivity; obesity; dopamine