Neoplasms, Adipose Tissue Clinical Trial
Official title:
The Effect of Sitagliptin on Brown Adipose Tissue and Whole-body Metabolism in Overweight Pre-diabetic Men
The obesity epidemic has resulted in an exponential increase in obesity-related disorders
including type 2 diabetes, dyslipidemia and cardiovascular disease. The associated morbidity
and mortality have major consequences both at an individual as well as on the socioeconomical
level. Thus, the development of novel therapies aimed at reducing the development of obesity
is highly warranted. Brown adipose tissue (BAT) recently emerged as a novel player in energy
expenditure in humans as it combusts fatty acids towards heat. Interestingly, obese subjects
have less BAT as compared to lean subjects and activation of BAT by means of intermittent
cold exposure reduces fat mass. Therefore, BAT is considered a promising novel target to
reduce obesity and associated disorders. As cold exposure is not the most desired therapeutic
strategy for humans, current pre-clinical research focuses on pharmacological activation of
BAT.
Interestingly, the investigators have recently shown that central agonism of the receptor for
the incretin hormone glucacon-like peptide-1 (GLP-1) results in activation of BAT in mice.
One of the currently used anti-diabetic drugs that enhances GLP-1 availability is Sitagliptin
(STG). Interestingly, STG also reduces body weight and plasma triglyceride (TG) levels in
type 2 diabetes mellitus (T2DM) patients. The mechanism underlying these beneficial metabolic
effects is currently unknown. The investigators hypothesize that STG enhances BAT activation,
thereby increasing energy expenditure and combustion of TG-derived fatty acids, resulting in
lowering of plasma TG levels and body weight.
To this end, the investigators will perform a randomized double-blinded placebo-controlled
study in which 30 male Dutch Caucasian adults aged 35-50 years with moderate obesity and
pre-diabetes are included. Subjects will be treated for 12 weeks with STG or placebo. Before
and after treatment, the investigators will determine BAT volume and total BAT activity via
cold-induced 18F-FDG PET-CT scans, resting energy expenditure via indirect calorimetry using
ventilated hoods, body weight, and body composition via DEXA scan. Furthermore, before and
after treatment, blood samples will be taken to measure plasma lipids, glucose and insulin
levels.
This study will offer valuable novel insight in the effects of pharmacological activation of
BAT in human obese subjects.
In the current study, the effect of 12 weeks of STG treatment (100 mg/day p.o.) versus
placebo will be studied in moderately obese pre-diabetic Dutch Caucasians males (35-50
years).
All study subjects will be screened and if the subject meets all the inclusion criteria, is
willing to participate in the study and has signed the informed consent, he will be included.
All subjects will be asked not to make any changes in their usual diets and physical
activities before the start of the whole study. Subjects will undergo two study days (day 1
and day 2) before STG or placebo treatment and two study days after treatment (day 84 and day
85) on which a cold-induced PET-CT scan as well as metabolic studies and skeletal muscle
biopsies are performed.
At screening a thorough medical history (see Appendix D) and physical examination will be
performed. Subjects will be examined while in the fasting state. Anthropometric measurements
will be performed as well as a basal blood sample will be taken by means of a venapunction.
Basal blood measurements include hematology and kidney, liver, thyroid and lipid parameters
as well as glucose, C-peptide and insulin concentrations. Thereafter, subjects ingest 75
grams of glucose orally (t=0) and at t=120 minutes a blood sample for the determination of
glucose, C-peptide and insulin will be drawn (venapunction) to assess glucose tolerance.
On study days 1 and 84, which take place at the dept. of Nuclear Medicine in the Rijnland
hospital, anthropometric measurements will be performed first, followed by ingestion of a
CoreTemp Pill for core temperature registration application, a DEXA scan, and application of
wireless iButtons to monitor skin temperature. Next, subjects will lay in a bed between two
water-perfused matrasses and water temperature will be set at 32°C (= thermoneutrality).
After 30 min of thermoneutrality, resting energy expenditure (REE) will be measured via
ventilated hoods. Then, thermoneutral venous blood samples will be obtained. Water
temperature will be gradually decreased and stabilized just above shivering level to induce
maximum non-shivering thermogenesis (NST) for the next two hours. During the cooling period,
blood pressure, heart rate and shivering are monitored at fixed intervals. At t=60 min, after
one hour of stable cooling, 110 MBq (2.09 mSv) 18F-fluorodeoxyglucose (FDG) will be injected.
At t=90 min, REE will be measured again. At t=120 min, cold-induced venous blood samples will
be obtained followed by performance of the PET-CT scan (see Appendix B for an overview of
study days 1 and 84).
On study days 2 and 85, which will be performed at the research laboratory at the LUMC, a
muscle biopsy will be taken first. Then, after 1 hour of rest, an OGTT will be performed. To
this end, a glucose drink containing 75 g of glucose will be ingested in maximum 5 minutes
and at t=-10, 0, 10, 20, 30, 40, 50, 60, 90 and 120 min venous samples will be taken to
assess glucose, insulin and C-peptide levels (see Appendix C for an overview of study days 2
and 85).
During the treatment period, study subjects will be called weekly by the researcher to ask
for possible side effects, signs of hypoglycemia, plasma glucose levels (via finger prick,
which will be done by the study subject himself) and compliance. Once a month, the study
subject will return to the research laboratory at the LUMC. During this occasion, next to the
above-mentioned parameters, also a venous blood sample will be obtained (venapunction) to
assess plasma glucose, insulin and triglyceride levels.
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