Is the Awakening Brain a Novel Therapeutic Target in the Treatment of Diabetes Mellitus type 2?

Insulin resistance and *b-cell failure are the hallmark of T2DM. While
compensating for *b-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.

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.

A single-arm intervention study.

Bromocriptine (DA D2 receptor agonist) orally once daily (<2 hours of
awakening) during 12 weeks (in 4 weeks the dose will be build-up to 5 mg 1dd,
which is then continued for another 8 weeks).

- Bromocriptine is a dopamine receptor agonist, that has been safely prescribed
for the treatment of Parkinson*s disease, hyperprolactinemia and galactorrhea
for many years. As discussed above, the most common side-effects of
bromocriptine are headache, sleepiness, dizziness, nausea, obstipation and
vomiting (*1:100, *1:10) [SmPC]. Side effects of hypotension, allergic reaction
of the skin, dry mouth, leg muscle cramps and fatigue are less frequently
reported (*1:1000, *1:100). Adverse events occur more frequently with
bromocriptine vs placebo ingestion, although this was only reported for the
titration phase. After the initial titration phase, commonly occurring adverse
events were reported at a frequency similar to that observed in the placebo
treated arm. In this trial participants will be frequently screened for
side-effects during both the titration and the stable phase of the
bromocriptine intervention. During the titration phase, the dose of
bromocriptine will only be increased when no side-effects are occurring. In
addition, bromocriptine has been shown to increase insulin sensitivity, reduce
the risk of cardiovascular events and to slow the progression of cardiovascular
disease in T2DM patients.
- IBZM has a European (CPMP) registration, and it has been shown that it has no
serious side effects. The dose equivalent per [123I]IBZM infusion amounts to
4.9 mSv (144 MBq). The total dose equivalent of the SPECT scan sessions (9.8
mSv) falls well within the maximum recommended dose equivalent for research
participants (i.e. 11.3 mSv and 15.3 mSv (WHO category IIb, females and males
resp., >50 years). Subjects will be provided with potassium iodide tablets on
the day before, and morning of the SPECT scans, in order to reduce iodide
uptake of the radioligand. Moreover, subjects are advised not to participate in
research using radiation imaging in the following year and/or when they are
exposed to radiation during their regular working duties.
- A low dose of i.v. dexamphetamine (0.3 mg/kg ideal bodyweight) has frequently
been administered in previous studies. It has been shown that while most
subjects experience large increases in happiness, restlessness and energy,
other subjects experience almost no subjective effects following 0.3 mg/kg
ideal bodyweight i.v. dexamphetamine, and that the quality and intensity of the
subjective responses to low dose amphetamine were similar during a second
exposure. Therefore, we can conclude that a low dose of 0.3 mg/kg ideal
bodyweight i.v. d-amphetamine, as will be administered in the present study,
will be well tolerated by the study participants. The subjective response to a
single dose of dexamphetamine includes an increase in feelings of: happiness,
energy, and a reduction in feelings of anxiety, and to a lesser extent some
restlessness.
To monitor potential somatic side effects, such as hypertension, palpitations,
tachycardia, cardiac arrhythmias and coronary spasms, subjects will be under
constant vital and ECG monitoring during and after the dexamphetamine
administration, in the presence of an experienced physician. Dexamphetamine
will be administered in the presence of a physician trained in resuscitation. A
twelve lead ECG, a code cart and defibrillator will be available. If the
systolic BP reaches or exceeds 200 mmHg for more than 5 minutes, nitroglycerine
will be administered sublingually to control the blood pressure and the
cardiologist on call will be notified. All subjects will be screened for the
presence of cardiovascular disease by interview, physical examination, ECG at
rest and during an exercise stress test.
- The stable isotope [6,6-2H2]glucose is used as a tracer, and has no
radioactive properties. It behaves like its natural substrate and has been
previously used without adverse effects when infused or ingested in tracer
amounts.
- During the hyperinsulinemic clamp there is a risk for hypoglycaemia. This is
minimised by close monitoring of plasma glucose levels, every 5-10 minutes.
- Venous blood draws can be an unpleasant experience for the participants. A
low risk of phlebitis at the needle site exists; this is unpleasant, however,
unharmful, of temporary nature, and self-limiting.

Worldwide, the prevalence of diabetes mellitus has quadrupled in the past
thirty years, and nowadays diabetes mellitus is the ninth major cause of death.
About 1 in 11 adults globally now have diabetes mellitus, 90% of whom have
T2DM. Most patients with T2DM have at least one complication, and
cardiovascular complications are the leading cause of morbidity and mortality
in these patients. Insulin resistance and *-cell failure are the hallmark of
T2DM. While compensating for *-cell failure with insulin treatment is effective
in reducing hyperglycemia and 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.
Studying the central regulation of glucose metabolism by brain dopaminergic
systems opens up new avenues and possibilities in the development of novel
therapies. Furthermore, restoring dopaminergic signalling with the aim to
reinstate normal dopamine daily rhythms and improve glucose regulation in
insulin resistant patients with T2DM is an attractive hypothesis to be studied
since dopamine agonists are well tolerated, safe and cheap. Finally,
bromocriptine has also been associated with beneficial effects on
cardiovascular outcomes and therefore may also prove useful in the prevention
of T2DM-related cardiovascular diseases.
We will keep the risks associated with participation to a minimum. Given the
expected results, we thus believe that the scientific value of our findings
will outweigh the burden and risks associated with participation.