The primary objectives of this study are: 1) To determine the effect of fasting-induced insulin resistance on cold-induced glucose uptake in brown adipose tissue; 2) To determine the effect of fasting on non-shivering thermogenic capacity; 3) To…
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Brief title
Condition
- Other condition
Synonym
Health condition
Geen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameters are:
- Standard uptake value (SUV) of BAT: This is used as a measure of BAT glucose
uptake and BAT activity and will be measured by means of FDG-PET/CT scanning.
- Skeletal muscle mitochondrial respiration/uncoupling: This will be determined
in skeletal muscle samples using the Oroboros 2k Oxygraph instrument present in
our laboratroy.
- Energy expenditure: This will be measured by means of indirect calorimetry
using a ventilated hood.
- Ex vivo skeletal muscle glucose oxidation: This will be measured to determine
insulin sensitivity. A glucose oxidation assay with insulin stimulation will be
performed in skeletal muscle biopsies.
Secondary outcome
Secondary study parameters include:
-Body temperatures: Skin temperatures will be measured by means of iButtons and
core temperature will be determined by ingestion of a telemetric pill.
- Skin perfusion: This will be measured by means of LaserDoppler flowmetry.
- Blood parameters: Venous blood will be drawn by means of a catheter placed in
the antercubital vein of the underarm. By using radioimmunoassay and high
performance liquid chromatography blood parameters will be analyzed.
- UCP-1 and beta3-receptor polymorphims
Background summary
Obesity and type 2 diabetes have emerged as two of the leading health problems
in modern western society. So far, simple non-surgical treatment strategies for
'diabesity' are very often ineffective. A promising new target for increasing
energy expenditure, and thus inducing weight loss, is facultative thermogenesis
(i.e. heat production when needed, e.g. in the cold) throught the activation of
brown adipose tissue (BAT). Recently, we have shown a negative correlation
between BAT activity upon mild cold exposure and body mass index (BMI),
suggesting that BAT might play a significant role in the development and/or
sustainability of obesity. Next to obesity per se, several animal studies and
retrospective human studies have suggested that diabetic status or insulin
resistance, the most important physiogical hallmark of type 2 diabetes, also
contribute significantly to cold-intolerance and reduced BAT activity. However,
no prospective studies so far have investigated the role of insulin resistance
in BAT activity upon mild cold exposure. In addition to BAT, skeletal muscle is
also suggested to play a role in non-shivering thermogenesis (NST), through the
process of mitochondrial uncoupling.
Study objective
The primary objectives of this study are: 1) To determine the effect of
fasting-induced insulin resistance on cold-induced glucose uptake in brown
adipose tissue; 2) To determine the effect of fasting on non-shivering
thermogenic capacity; 3) To determine the effect of fasting on skeletal muscle
mitochondrial uncoupling and how this is related to non-shivering
thermogenesis.
Study design
The study will include 2 PET/CT scans for each individual, in which
cold-induced BAT activity will be measured: the first scan will be performed
after a normal-fed period and the second scan will be performed after a 54-h
fasting period (to induce insulin resistance). Both scanning protocols consist
of a dynamic and static PET/CT scan. To investigate the role of mitochondrial
uncoupling in skeletal muscle in cold-induced thermogenesis, muscle biopsies
wil be taken in both conditions. Thermogenesis will be measured using indirect
calorimetry and the insulative response will be determined by thermometry and
skin perfusion.
Intervention
Fasting period of 54 hours to induce severe insulin resistance in healthy
subjects. The insulin resistance is temporarily and fully reversible.
Study burden and risks
The risks of this experiment will be low.
The total exposure to radioactive radiation due to the administation of 18F-FDG
for the PET/CT scans is 6,4 mSv for the total study. This is equal to about 3
times the total annual background radiation in the Netherlands and is
considered as a low risk and fully acceptable for medical scientific research
by the International Commission on Radiological Protection (<10 mSv). Thus, the
risk of health damage is very limited.
Universiteitssingel 50
Maastricht 6229 ER
NL
Universiteitssingel 50
Maastricht 6229 ER
NL
Listed location countries
Age
Inclusion criteria
Healthy, lean (BMI 18-25 kg/m2) adults
Age: 18-30 years
Male and female
For females: use of a specific oral contraceptive (Microgynon 30 or levonorgestrel/ethinylestradiol)
Caucasian
Sedentary (=< times/week or =< 3 hours/week sports)
Exclusion criteria
Cardiovascular diseases
Hypertension (systolic/diastolic blood pressure > 140/90)
Hypotension (systolic/diastolic blood pressure <90/60)
Use of beta-blockers
Asthma or other obstructive pulmonary diseases
Diabetes Mellitus type 1 and type 2
Elevated blood glucose levels (>5.6 mmol/l)
Hyperthyroidism
Pregnancy
Participation in earlier research or medical examinations that included PET/CT scanning
Radiation therapy due to medical treatment
Unstable body weight (weight gain or loss >3kg in the past 2 months)
Any known or suspected obstructive disease of the gastrointestinal tract, hypo motility disorders of the gastrointestinal tract or previous gastrointestinal surgery.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | Nederlands Trialregister: TC = 3523 |
| CCMO | NL39816.068.12 |