Bromocriptine bij type 2 diabetes mellitus

Insulin resistance and b-cell failure are the hallmark of T2DM. While compensating for -cell failure with insulin treatment is effective in reducing hyperglycemia and haemoglobin A1C (HbA1C), it has serious side effects (i.e. hypoglycaemia, body weight gain) and poses a burden for the patient. Reducing insulin resistance in diabetes patients would be another logical target, but most treatment modalities have either no or modest effect on insulin sensitivity. Moreover, the lack of detailed knowledge on the pathophysiology of insulin resistance in humans is hampering the development of novel therapies. For many years, diabetes research has focussed on peripheral determinants of insulin sensitivity and although these often ground-breaking discoveries in animals led to useful novel insights in insulin signalling, translation to clinical treatment is still scarce. The brain as master regulator of energy metabolism has long been ignored in clinical diabetes research. It has been shown however that dopaminergic signalling is disturbed in obesity and we have recently shown that stimulation of striatal dopaminergic signalling improves insulin sensitivity. We here aim to follow the physiology of daily rhythmic dopamine release in reducing insulin resistance in T2DM. Furthermore we will explore the potential of bromocriptine, a dopamine agonist, as a therapeutic option for T2DM. Objective: With this proof-of-concept study, we will address i. differences in dopamine release in T2DM patients versus historical lean controls, ii. whether timed restoring of dopamine signalling improves dopamine release and iii. whether this reinstatement of daily dopamine rhythms is associated with an improvement in insulin sensitivity. We hypothesize that in patients with T2DM i. dopamine release is reduced in comparison to a cohort of matched historical healthy and lean controls, ii. restoring the peak in morning dopamine signalling will partially restore dopamine release, and iii. this increase in dopamine release is associated with an increase in insulin sensitivity. Study design: a single-arm intervention study. Study population: we intend to include 40 T2DM patients, aged 50-70 years. Intervention: Bromocriptine (Dopamine D2 receptor agonist) orally, once daily (within 2 hours after awakening) during 12 weeks (in 4 weeks the dose will be up titrated to 5 mg, which is then continued for another 8 weeks). Main study parameters/endpoints: The effect of the bromocriptine intervention on i. dexamphetamine-stimulated dopamine release (SPECT imaging; ∆ D2/3R BPND), and ii. insulin sensitivity of adipose tissue, liver and skeletal muscle (hyperinsulinemic, euglycemic clamp; percentage of insulin-induced suppression of free fatty acids (FFA) and endogenous glucose production (EGP), and insulin-stimulated rate of disappearance, respectively). Furthermore, we aim to assess the correlation between bromocriptine-induced changes in stimulated dopamine release and changes in insulin sensitivity.

We hypothesize that in patients with T2DM i. dopamine release is reduced in comparison to a cohort of matched historical healthy and lean controls, ii. restoring the peak in morning dopamine signalling will partially restore dopamine release, and iii. this increase in dopamine release is associated with an increase in insulin sensitivity.

A total of 8 visits: Visit 1 Visit 2 and 3 Visit 4 after 2 weeks Visit 5 after 4 weeks Visit 6 after 8 weeks Visit 7 after 12 weeks Visit 8 after 13 weeks

Bromocriptine orally, once daily during 12 weeks