Obesity Clinical Trial
Official title:
The Effect of Mirabegron on Brown Adipose Tissue in Healthy Young White Caucasian and South Asian Men
Obesity and type 2 diabetes (T2D) are emerging problems worldwide. In particular South Asian
individuals (representing 20% of the world population) have an increased risk of obesity and
related disorders. They are at higher risk for the development of T2D as compared to white
Caucasians and develop T2D at a younger age and with lower BMI. The underlying mechanisms
that might explain these ethnical differences have not been clarified or understood yet. As
a consequence, treatment options are limited and unfocussed, and novel specific strategies
are needed.
Brown adipose tissue (BAT) has recently been discovered as a major player in energy
metabolism in humans. In a process known as thermogenesis, BAT takes up fatty acids (FA) and
glucose from the circulation and subsequently combusts FA and glucose into heat, thereby
increasing energy expenditure and improving glucose and FA metabolism. Using
18F-fluorodeoxyglucose (18F-FDG) (positron emission tomography/computed tomography) PET-CT
scan analysis investigators have recently shown that South Asian individuals have less brown
adipose tissue (BAT) than white Caucasians. This might suggest that they have a lower energy
metabolism, which could underlie their increased predisposition for obesity and the
development of T2D.
Activation of BAT, for example by cold exposure, was shown to have beneficial metabolic
effects in humans. Cold acclimatization can increase BAT volume, nonshivering thermogenesis,
glucose uptake by BAT, as well as decrease fat mass in healthy young men. Therefore
activation of BAT is considered as a novel therapeutic target in the treatment of obesity
and T2D. As cold exposure is not the most desired therapeutic strategy for humans, current
pre-clinical research focuses on pharmacological activation of BAT.
β3-receptor agonists can be used to mimic sympathetic innervation of BAT. Our recent studies
using mice with a human-like lipoprotein profile showed that treatment with a β3-receptor
agonist decreased fat mass, improved dyslipidemia, increased insulin sensitivity and even
attenuated the development of atherosclerosis. Likewise, the novel β3-receptor agonist
(Mirabegron) has recently been shown to activate BAT in healthy young men as effectively as
cold exposure. Therefore, ß3-receptor agonism would be a promising treatment option to
activate BAT and enhance energy expenditure, especially for South Asians.
Currently the most common way to visualize BAT in humans is by 18F-FDG PET-CT scan. However
this method is both expensive and invasive, as it uses ionizing radiation. Recently, MRI,
which has no radiation burden, has emerged as a novel method to visualize BAT in humans.
Activation of BAT results in combustion of intracellular lipid stores, which eventually
leads to a lower triglyceride (TG) content. MRI can measure TG content of tissue, and using
MRI technology the activation of BAT can be quantified by the relative reduction in the TG
content of BAT. The use of MRI to visualize and quantify BAT activity is a safe,
cost-effective and innovative alternative to PET-CT, which has a potential to become a new
gold standard in the nearby future.
To investigate whether β3-receptor agonism has therapeutic potential to improve the
metabolic phenotype of South Asians, investigators will perform a randomized cross-over
study in which 20 healthy young men aged 18-30 years with a lean body type (BMI <25 kg/m2)
are included. Dutch South Asian individuals (n=10) and matched Dutch white Caucasian
individuals (n=10) will participate in a cross-over study consisting of three different
regimes.
This study will investigate whether β3-receptor agonism has therapeutic potential to improve
the metabolic phenotype of South Asians. The effects of a β3-receptor agonist on BAT
activity in South Asians have never been studied before. Elucidating the effects of this
β3-receptor agonist on BAT activity in South Asians might have major clinical implications,
as it might result in the discovery of a potential novel treatment strategy to combat
obesity and T2D in this especially vulnerable population.
In the current study, the effect of one single dose of Mirabegron (200 mg) versus placebo
and cold-exposure will be studied in health young (18-30 years) Dutch South Asian (n=10) and
Dutch Caucasian (n=10) men.
All study subjects will be screened. 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.
At screening a thorough medical history and physical examination will be performed. Subjects
will be examined while in the fasting state. Anthropometric measurements will be performed
as well as a BIA measurement for determination of body fat percentage and basal blood sample
will be taken by means of a venapunction. Basal blood measurements include kidney, liver,
thyroid, hemoglobulin, natrium, kalium, ureum and lipid parameters as well as glucose
concentrations.
If subjects are eligible to participate they first will complete Study day 1, on which we
will measure BAT activity and volume before and after cold exposure. Subject will undergo a
baseline oxycon and finapres measurement to determine REE and blood pressure and heart rate
(30 min). After this a baseline MRI scan will be made followed by an individualized cooling
protocol so that the maximum non-shivering thermogenesis is reached. During the cold
exposure, skin temperature will be measured via 'iButtons'. One iButtons will be placed
under the armpit as an approximation of the 'core temperature'. When shivering temperature
is reached, stable cooling period will start (t=0). After 30 minutes of stable cold exposure
(t=30) REE and blood pressure and heart rate will be analyzed a second time using a
ventilated hood system and the finapres. Thereafter (t=60) BAT activity and volume will be
measured using a second MRI scan. Furthermore, during the cooling procedure a venous blood
sample will be obtained every 15 minutes to monitor dynamic changes in plasma lipids. In
addition, plasma catecholamine concentrations will be determined. If there is no increased
BAT activity upon cold stimulation the subject will be excluded from further participation
in the study. If there is detectable BAT activity on Study day 1, subjects will participate
in Study days 2 and 3 and will be randomized to receive first Mirabegron or placebo to
minimize bias.
On study day 2 first baseline oxycon and finapres measurements will be performed to
determine REE and blood pressure and heart rate (30 min). Thereafter, the subject will
receive a single dose of 200 mg Mirabegron (four tables of 50 mg) (or placebo) (t=0). Again
skin temperature will be measured via 'iButtons'. One iButton will be placed under the
armpit as an approximation of the 'core temperature'. After 1, 2 and 3 hours (t=60, t=120
and t=180) REE is analyzed using a ventilated hood system and blood pressure and heart rate
are monitored using the finapres. Thereafter, 3.5 hours after the administration of the
compound (t=210) BAT activity and volume will be determined using an MRI scan. Furthermore,
a venous blood sample will be drawn every 15 minutes to monitor changes in plasma lipids. In
addition, plasma catecholamine concentrations will be determined.Study day 3 is exactly the
same as study day 2, except this time the subject will receive the other compound (either
200 mg Mirabegron or placebo).
All study days will take place at the Leiden University Medical Centre (LUMC). Between study
days 2 and 3 a wash-out period of 13 days will be maintained to make sure that the drug is
out of the body during the next exam.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT04243317 -
Feasibility of a Sleep Improvement Intervention for Weight Loss and Its Maintenance in Sleep Impaired Obese Adults
|
N/A | |
Recruiting |
NCT04101669 -
EndoBarrier System Pivotal Trial(Rev E v2)
|
N/A | |
Terminated |
NCT03772886 -
Reducing Cesarean Delivery Rate in Obese Patients Using the Peanut Ball
|
N/A | |
Completed |
NCT03640442 -
Modified Ramped Position for Intubation of Obese Females.
|
N/A | |
Completed |
NCT04506996 -
Monday-Focused Tailored Rapid Interactive Mobile Messaging for Weight Management 2
|
N/A | |
Recruiting |
NCT06019832 -
Analysis of Stem and Non-Stem Tibial Component
|
N/A | |
Active, not recruiting |
NCT05891834 -
Study of INV-202 in Patients With Obesity and Metabolic Syndrome
|
Phase 2 | |
Active, not recruiting |
NCT05275959 -
Beijing (Peking)---Myopia and Obesity Comorbidity Intervention (BMOCI)
|
N/A | |
Recruiting |
NCT04575194 -
Study of the Cardiometabolic Effects of Obesity Pharmacotherapy
|
Phase 4 | |
Completed |
NCT04513769 -
Nutritious Eating With Soul at Rare Variety Cafe
|
N/A | |
Withdrawn |
NCT03042897 -
Exercise and Diet Intervention in Promoting Weight Loss in Obese Patients With Stage I Endometrial Cancer
|
N/A | |
Completed |
NCT03644524 -
Heat Therapy and Cardiometabolic Health in Obese Women
|
N/A | |
Recruiting |
NCT05917873 -
Metabolic Effects of Four-week Lactate-ketone Ester Supplementation
|
N/A | |
Active, not recruiting |
NCT04353258 -
Research Intervention to Support Healthy Eating and Exercise
|
N/A | |
Completed |
NCT04507867 -
Effect of a NSS to Reduce Complications in Patients With Covid-19 and Comorbidities in Stage III
|
N/A | |
Recruiting |
NCT03227575 -
Effects of Brisk Walking and Regular Intensity Exercise Interventions on Glycemic Control
|
N/A | |
Completed |
NCT01870947 -
Assisted Exercise in Obese Endometrial Cancer Patients
|
N/A | |
Recruiting |
NCT06007404 -
Understanding Metabolism and Inflammation Risks for Diabetes in Adolescents
|
||
Recruiting |
NCT05972564 -
The Effect of SGLT2 Inhibition on Adipose Inflammation and Endothelial Function
|
Phase 1/Phase 2 | |
Recruiting |
NCT05371496 -
Cardiac and Metabolic Effects of Semaglutide in Heart Failure With Preserved Ejection Fraction
|
Phase 2 |