Bromocriptine and Insulin Sensitivity (the BIS study)

Obesity and diabetes mellitus type 2 (DM2) are health problems with a
tremendous impact. Many attempts have been made to combat obesity and DM2,
however, a breakthrough therapy is still lacking.
Bromocriptine, a dopamine 2 receptor agonist, has recently been approved in the
treatment of DM2. Bromocriptine causes a significant improvement of fasting
plasma glucose and Hba1C values. The exact mechanism of action of bromocriptine
is still unknown.
Earlier, we performed a study to show the effects of bromocriptine on brown
adipose tissue (BAT) activity (the DEBAT study 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, we have shown that
bromocriptine did not influence BAT activity or energy expenditure in healthy,
lean subjects.
We 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 we instructed the subjects to use the bromocriptine in the evening in
combination with the evening meal. We decided to do so because bromocriptine
had to be taken in combination with food. We wanted a high level of dopamine
just before the 18F-FDG-PET-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, we 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.

Primairy objective: To determine whether there is a beneficial effect on
insulin sensitivity when bromocriptine is given in the morning, as compared to
bromocriptine in the evening in Caucasian, lean and obese males.
Secondary Objectives:
1. To determine whether there are differential effects of bromocriptine
treatment on insulin sensitivity in obese or lean healthy, Caucasian males.
2. To determine whether the difference in timing of bromocriptine influences
energy expenditure during thermoneutral conditions in Caucasian, lean and obese
males.

Randomized physiology study.

Study Design: Observational design with invasive measurements, randomized study
physiology.
Volunteers will come to the AMC four times, each visit will take about 3.5-4
hours:
At each visit a canlua will be placed, energy consumption will be measured by
indirect calorimetry and an OGTT will be performed.
The insertion of the canulacan be experienced as unpleasant and there is a
small chance of developing a phlebitis at the location of the canula.
Also, the subjects could experience side effects of the bromocriptine. There is
no direct benefit to the volunteers.