The effect of Exenatide on brown adipose tissue activity and energy expenditure in healthy young men

The obesity epidemic has led to a enormous increase in the prevalence of type 2
diabetes mellitus (T2D), dyslipidemia and cardiovascular events. Particularly
South Asians, who comprise 1/5 of the world population, are at increased risk
of developing a disadvantageous metabolic phenotype and these diseases.
Moreover, T2D occurs at a younger age and at a lower BMI when compared to white
Caucasians. Recent research has shown that South Asians not only have a lower
energy expenditure than their white Caucasian counterparts, but also less
active brown adipose tissue (BAT).

For some time, it has been known that adult humans have active BAT. This
metabolic tissue produces heat by combusting triglycerides, in contrast to
white adipose tissue, which stores this form of energy. It has been shown that
activation of BAT has a positive effect on whole body metabolism, via
increasing energy expenditure and improving glucose- and lipid metabolism. For
this matter, BAT has been proposed as a major key player in energy homeostasis,
which may be implemented in the current combat against the obesity epidemic.

Aside from cold exposure, more research focuses on pharmacological activation
of BAT. Glucagon-like peptide 1 (GLP-1) is an incretin hormone which is
produced by intestinal L-cells and upon food intake stimulates insulin
secretion by pancreatic beta cells. The GLP-1 analogue Exenatide is a currently
much used antidiabetic drug to reduce hyperglycemia via this aforementioned
mechanism. Beyond its blood glucose-improving effects, Exenatide has also shown
to lower body weight and improve dyslipidemia in T2D patients. Elucidation of
the underlying mechanism of these beneficial effects is highly relevant.

Recent preclinical research in our group has shown that central activation of
the GLP-1 receptor through Exenatide increases BAT activity and thereby
contributes to weight loss and improvement of dyslipidemia. The aim of this
research project is to investigate whether Exenatide is also able to activate
BAT and increase resting energy expenditure, thereby improving glucose- and
lipid metabolism and reducing fat mass and body weight in humans. Moreover, we
aim to validate the MRI scan as a novel way to measure BAT activity. We hope
that these forthcoming findings lead to the discovery of new treatment
strategies against obesity.

Primary objective
- To evaluate the effect of Exenatide treatment on brown adipose tissue
activity and energy expenditure in healthy young Dutch male subjects of South
Asian and white Caucasian descent.

Secondary objective
- To validate the MRI scan as a novel technique for measuring brown adipose
tissue activity

Open-label single arm prospective study with 24 healthy young lean males (BMI *
18 and *27 kg/m2), of whom 12 Dutch South Asians and 12 Dutch Caucasians. After
a screening, included subjects will receive 12 weeks of treatment with the
GLP-1 analogue Exenatide (Bydureon; 2 mg s.c. 1x/wk). Study subjects will visit
the LUMC weekly during the first 4 weeks, where the injection will be
administered under the supervision of the researcher, to maximize compliance
and monitor the injection technique. If the researcher is confident that
subjects are able to administer the injections themselves without supervision,
subjects can administer the medication at home for the final 8 weeks and will
be called weekly to monitor possible side effects and compliance. Before and
after treatment there will be a study day, in which brown adipose tissue
activity (by means of 18F-FDG PET-CT scan and MRI scan), resting energy
expenditure (thermoneutral and after being exposed to mild cold, measured by
indirect calorimetry) and fat mass (by bio-impedance analysis) will be
measured. Per study day, two blood draws will take place in order to
investigate the effects of Exenatide on lipid- and glucose metabolism.

Study subjects will receive Exenatide treatment during 12 weeks, via a weekly 2
mg subcutaneous injection. During both study days, subjects will be exposed to
2,5 hours of very mild cold.

Each subject will undergo a medical screening (including a medical history
questionnaire, physical examination, anthropometric measurements and a basal
blood sample by means of a venapunction), followed by one study day before and
one after 12 weeks of treatment with Exenatide via a subcutaneous injection of
2 mg once a week. During the first 4 weeks, subjects will visit the LUMC weekly
and the Exenatide injection will be performed under supervision of the
researcher. If the researcher is convinced that subjects are able to perform
the injection adequately, the last 8 injections can be performed by the
subjects themselves at home. In that case, the researcher will contact the
subject weekly by telephone and ask for compliance and possible side-effects.
One week after ending of the study, a follow-up phone call will take place.

Per study day, the following measurements will take place:
- Noninvasive antropometric measurements (blood pressure, body weight)
- One bio-impedance analysis measurement (noninvasive method to measure fat
mass)
- Two times indirect calorimetry measurement (noninvasive method of measuring
energy expenditure by means of placing a transparent light-weighted plastic
hood over the subject's head)
- Measurement of tissueoxygenation via PortaMon (noninvasive method via near
infrared spectroscopy)
- Two blood draws. There is a risk of developing a hematoma at the place of the
intravenous catheter.
- Exposure to two and a half hours of mild cold (by laying in a bed between two
water-perfused mattresses)
- One MRI scan to measure BAT activity and liver fat. For this purpose, one
time a MRI questionnaire will be taken beforehand.
- One 18F-FDG-PET-CT scan to measure BAT volume and activity, which for both
study days together accounts for a total radiation burden of 8.0 mSv and is
considered a low risk according to the current ICRP guideline of the European
Committee (category IIb, risk due to radiation burden of maximally five in ten
thousand). In line with this, our research concerns acquisition of knowledge,
aimed at prevention or cure of a disease and serves a collective purpose for
the community.

Between the study days, participants will fill in a food diary 4 times for 1
day and 4 times a hunger and satiety questionnaire.

The most common side effects of Exenatide are gastrointestinal complaints. At
site of the injection, an itchy rash and/or erythema may appear. If these
potential side-effects occur, they are expected to disappear within a few
weeks. A rare side effect of Exenatide is acute pancreatitis. Patients are
informed on possible symptoms and the researchers will ask for these during the
weekly contact. There is also the risk of hypoglycemia, which is not to be
expected however, since this is mostly the case when using concomitant
glucose-lowering drugs (especially sulphonylurea derivates), and this is not
the case in the study subjects. All subjects will be made aware of possible
symptoms and will be provided with a glucose meter and instructions. The
researchers will also ask for these symptoms and check for compliance during
the weekly contact.