Visualizing differences in cerebral dopamine- and serotonin transporters between lean subjects and obese subjects with normal- and decreased insulin sensitivity

The role between obesity, insulin resistance (IR) and the brain has been of
interest for several years. In recent years, research suggests a role for
cerebral dopamine and serotonin. From animal- and some humane research it has
become clear that there is ground for the hypothesis that cerebral dopamine
transporter (DAT) and serotonin transporter (SERT) are related to both BMI and
glucose metabolism. SERT- and DAT knockout mice have an obese phenotype. In
humans, we found that SSRI treatment (inhibiting serotonin reuptake via SERT)
improves insulin resistance. In addition, treatment with a dopamine agonist in
hamsters reduced hyperinsulemia and body weight gain. We are able to measure
cerebral SERT and DAT in humans with SPECT using the radioligand [123I]FP-CIT.

We hereby hypothesize that obesity results in an increase in cerebral SERT and
DAT, compared to healthy controls. Cerebral SERT and DAT increase will be more
prominent in insulin resistant obese subjects compared to obese subjects with
normal insulin sensitivity.

Observational study

[123I]FP-CIT used in the SPECT-scans has a European (CPMP) registration. In the
trials preceding the marketing authorization it has been shown that no serious
side effects occur after administration of this radioligand. (Booij et al.
24-30). To minimize uptake of the radioligand in the thyroid, kaliumiodide
tablets are provided to study participants on the day before- and morning of
the scan. Subjects will be exposed to radiation of 2.7 mSv. To assess the risks
of exposure to radiation, we asked for a radiation advice by the department of
radiology of the AMC. This was sent to the local METC apart from the study
protocol and states that radiation exposure as a consequence of this study is
mediocre (WHO Class IIb). The MRI-scan requires lying still as possible for 15
minutes on a solid plate, which might cause minor discomfort. There are no
expected advantages as a consequence of study participation.

It is well known that treatment and prevention of obesity and T2DM is far from
being effective. The obesity epidemic is progressing with all its consequences.
We therefore think it is of utmost importance to contribute to better
understanding and possibly better treatment and prevention. To show the role of
SERT and DAT in obesity and changes in glucose metabolism would mean whole new
insights on pathophysiologal mechanisms. Moreover, better pathophysiological
insight might lead to new, improved treatment of obesity and type 2 diabetes
(T2DM). It could also lead to newer and more preventive strategies. To answer
our study questions and contribute to unravelling the pathophysiological
pathways of obesity and insulin resistance in a reliable way, the use of
SPECT-scan with the named amount of radiation is inevitable. There are no known
circulating markers which reflect quantitative measures of the dopaminergic or
serotonergic pathways in the brain. Imaging is the only way to study this.