To investigate whether 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.
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the effect of sitagliptin treatment on BAT activity (measured via
cold-induced 18F-FDG PET-CT scans)
Secondary outcome
To assess the effect of sitagliptin treatment on 1) resting energy expenditure,
2) muscle glucose metabolism, 3) fat mass, 4) glucose metabolism, and 5) plasma
lipid levels in overweight, pre-diabetic subjects.
Background summary
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, we 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. Of note, enhancing GLP-1 availability is currently a therapeutic
strategy to treat type 2 diabetes as it, amongst others, enhances insulin
secretion. One of the currently used anti-diabetic drugs that enhances GLP-1
availability is Sitagliptin (STG). STG increases GLP-1 availability by
inhibiting breakdown of dipeptidylpeptidase-4 (DPP-4), the enzyme that
hydrolyzes GLP-1 and hence normally results in only short availability
(half-life approx. 1.5 min) of endogenous GLP-1. 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.
Study objective
To investigate whether 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.
Study design
We will perform a randomized double-blinded placebo-controlled study in which
30 male Dutch Caucasian adults aged 35-55 years with moderate obesity and
pre-diabetes are included. Subjects will be treated for 12 weeks with STG or
placebo. Before and after treatment, we 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. After 4 and 8 weeks
of treatment, the will be a check-up and resting energy expenditure will also
be measured via indirect calorimetry.
Intervention
Sitagliptin (100 mg/day p.o.) for 12 weeks. The medication will be given to the
subjects all at once.
Study burden and risks
- There is a risk for the participant of getting a haematoma after the muscle
biopsy if the biopsy has not been executed well
- There is a risk for the participant of getting a heamatoma after placing the
catheter
- The most frequently reported side-effects of sitagliptin are upper
respiratory infections and headache. In addition, hypoglycemia might occur but
this is mostly the case when concomitant glucose-lowering drugs, especially
sulfonylurea derivatives are used. This is not the case in our subjects. We
will make sure that our subjects are aware what symptoms of hypoglycemia are
and will provide them with a glucose meter.
- The effective dose of the PET/CT procedure and DXA-scan is 9.38 mSv, which is
considered a low risk. Due to participation in this study, the subjects cannot
participate in other research that involves radiation
Waarderweg 3 39
Haarlem 2003 PC
NL
Waarderweg 3 39
Haarlem 2003 PC
NL
Listed location countries
Age
Inclusion criteria
- Male volunteers, 30 Caucasians, born in the Netherlands
- Age: 35-55 years
- BMI * 25 and * 35 kg/m2
- Plasma glucose levels 2 h after OGTT between 7.8 and 11 mM (e.g. impaired glucose tolerance) or fasted plasma glucose >5.6 mM
Exclusion criteria
- Diabetes mellitus (determined on basis of oral glucose tolerance test (OGTT) defined by ADA criteria
- BMI > 35 kg/m2 or < 25 kg/m2
- Plasma glucose levels 2 h after OGTT < 7.8 mM or > 11.1 mM
- Use of medication known to influence glucose and/or lipid metabolism or BAT activity (e.g. beta blockers)
- Any significant chronic disease
- Renal, hepatic or endocrine disease
- Smoking
- Participation in an intensive weight-loss program or vigorous exercise program during the last year before the start of the study
- Difficulties to insert an intravenous catheter
- Recent participation in other research projects (within the last 3 months), participation in 2 or more projects in one year
Design
Recruitment
Medical products/devices used
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003532-39-NL |
| CCMO | NL50531.058.14 |