Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT04060745 |
| Other study ID # |
Brown fat imaging |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2019 |
| Est. completion date |
December 1, 2022 |
Study information
| Verified date |
May 2021 |
| Source |
University of Aarhus |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In this study the investigators wish to evaluate the glucose metabolism in brown adipose
tissue (BAT) in young healthy men (aged 18-35). The investigators wish to validate a novel MR
modality - Deuterium Metabolic Imaging (DMI), which is a non-radioactive, non-invasive method
that allows for spatial as well as metabolic imaging after oral administration of
deuterium-labelled glucose. Deuterium is a stable isotope of hydrogen that can be bound to
different metabolites, in this case glucose. This method allows for metabolic imaging and
production of 2H MR spectra of metabolites downstream from glucose uptake that can be
quantified. DMI has not yet been used to evaluate BAT in humans. Currently, FDG PET/CT is the
most widely used method for BAT evaluation in humans, but due to the radiation-exposure
associated with FDG PET/CT repetitive studies of BAT in healthy subjects are limited.
Therefore, new in vivo methods (preferably non-invasive) are warranted.
However, since FDG PET/CT is the most widely used method, the investigators wish to use this
modality as reference.
The investigators plan to screen 10-12 subjects with an individualized cooling protocol and
FDG PET/CT. Only the BAT positive subjects will be included in the DMI study. In the DMI
study, the BAT positive subjects will enter in a randomized two-phased cross-over study. The
subjects will have 2 DMI scans performed after ingestion of deuterium-labelled glucose; one
after 2h of cooling, another in thermoneutrality. Primary outcome is the differences in
glucose metabolites between cooling and thermoneutrality. The investigators hypothesize that
during cooling uptake of glucose and its metabolites such as glutamine/glutamate and water
may be enhanced. Moreover, glucose metabolism may shift towards anaerobic metabolism with
increased lactate production as observed in a previous rodent study by the investigators
group.
Description:
The prevalence of obesity and type 2 diabetes has increased exponentially over the past
decades giving rise to substantial individual as well as health economic costs. Therefore,
more research are warranted in the development of new prevention and treatment strategies.
In 2009 findings using 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (FDG-PET)
verified the presence of metabolically active brown adipose tissue (BAT) in adult humans and
since then BAT has been revitalized as a potential target organ in the treatment of obesity
and metabolic syndrome. Through increased activity of the sympathetic nervous system (SNS)
and the corresponding release of norepinephrine (NE), cold is among the most potent
physiological activators of BAT, but other stimulating factors such as natriuretic peptides,
BMP8b, COX2, bile acids, thyroid hormones, FGF21 and even bioactive food components are
known. Activated BAT increases the energy expenditure via uncoupling (via uncoupling protein
1 - UCP1) of the inner mitochondrial membrane resulting in leak of electrons and heat
production at the expense of ATP production (non-shivering thermogenesis) a mechanism
evolutionary developed to sustain body temperature. It is known that age, gender, degree of
obesity and insulin resistance is associated with BAT activity. Furthermore, activated BAT
generally improves glucose tolerance, insulin sensitivity and promotes weight loss in rodent
models giving rise to hopes for similar effects in humans. However, deeper insight into in
vivo BAT metabolism in humans are still warranted. BAT is anatomically located along the
major vessels, surrounding the large organs, the anterior neck, sub-clavicular, axillary and
in the inguinal fossa. In this proposed clinical study, the investigators wish to examine the
anterior neck and supraclavicular area that are known to comprise the largest BAT depots.
When BAT is activated glucose- as well as free fatty acids uptake are greatly increased
compared to non-activated BAT and therefore the most widely used method for in vivo
assessment of BAT activity and imaging in humans is currently FDG PET/CT. This well-known
imaging modality relies on the radioactive glucose tracer 18FDG to detect tissues with high
glucose consumption e.g. activated BAT. The 18FDG signal gives an indication of the
distribution of glucose uptake and phosphorylation in the tissue. However, FDG PET imaging
does neither provide information on spatial metabolic activity, nor the different metabolites
downstream from glucose as FDG is not further metabolized when taken up in the tissue.
Moreover, due to the radiation-exposure associated with FDG PET/CT repetitive studies of BAT
in healthy subjects are limited.
New in vivo methods (preferably non-invasive) are warranted in order to reveal the true
potential of targeting BAT thermogenesis to prevent and/or treat cardio metabolic disorder.
To accommodate this need, Deuterium Metabolic Imaging (DMI) may be a potential tool. DMI is a
novel non-radioactive, non-invasive method that allows for spatial as well as metabolic
imaging after oral administration of [6,6'- H ]-glucose. Deuterium is a stable isotope of
hydrogen that can be bound to different metabolites, in this case glucose. This method allows
for metabolic imaging and production of 2H MR spectra of metabolites downstream from glucose
uptake that can be quantified. The method has already been applied in studies of the human
and rat brain using spectroscopic imaging at 4T and 11.7T respectively, but has never been
used to assess glucose metabolism in human BAT.
The acquired spectra from DMI contain peaks of [2H]glucose, [2H]lactate, [2H]-Glx, which
contains signals from [4,4´-2H2]glutamate, [4-2H]glutamate, [4´-2H]glutamate,
[4,4´-2H2]glutamine, [4´-2H]glutamine and [4´-2H]glutamine and finally [2H]water.
The biochemical pathway of the labelled [2H] is as followed: When [6,6'- 2H2 ]-glucose is
taken up in the tissue the [2H] is firstly incorporated into pyruvate to form
[3,3-2H]Pyruvate through glycolysis. Under anaerobic circumstances [3,3-2H]Pyruvate is
secondly converted to [3,3-2H]lactate catalyzed by lactate dehydrogenase (LDH).
[3,3-2H]Pyruvate can also be transported into the mitochondria and be transformed into
[2,2-2H]Acetyl-CoA catalyzed by pyruvate dehydrogenase (PDH). When entered into the TCA
cycle, the intermediates of [4-2H] or [4,4-2H]Citrate and [4-H] or [4,4-2H]α-ketoglutarate
will be produced. The latter may exchange with glutamate to generate [4-H] or
[4,4-2H2]glutamate. From the TCA cycle, 2H-labeling may depart and exchange with the protons
in water molecules to generate [2H]water.
Prior to this proposed clinical trial, the investigators have recently conducted a rodent
study to test the method (data not yet published).
The investigators show that DMI of the interscapular BAT depot in cold-acclimatized rats
reveals increases in all [²H]-labelled metabolites after [6,6'-²H₂]-glucose infusion
(glucose, glutamine/glutamate, lactate and water) indicating an overall increase in uptake
and glucose metabolism with higher glutamine/glutamate and lactate production in cold
acclimatized rats compared to thermo-neutral rats. These metabolites potentially originate
from an elevated TCA cycle flux and an associated increased anaerobic metabolism in the
cold-acclimatized rats. The investigators hereby show that DMI can be used to discriminate
between activated and non-activated BAT in rats. These findings are supported by increased
mean fat/water threshold in cold-acclimatized rats compared to thermo-neutral rats indicating
an increased water content or vascularization. Furthermore, a robust 13-fold increment in the
specific thermogenic marker uncoupling protein one (UCP1) mRNA expression was found in BAT
biopsy material of cold-acclimatized rats.
These results indicate that DMI of BAT in humans are feasible.
Aim/perspectives To evaluate if DMI can be used to assess and discriminate glucose metabolism
in activated and non-activated BAT in humans using a randomized controlled crossover design
in healthy young men in order to use this method to determine BAT activity in humans .
The investigators hypothesize that in cold activated BAT glucose metabolism will increase as
measured by increase in uptake and metabolism resulting in increase in glucose,
glutamate/glutamine and water. Moreover, glucose metabolism may shift from aerobic metabolism
towards anaerobic metabolism with increased lactate production in activated BAT as observed
in the rodent study.
This non-invasive, non-radioactive method may pave the way for future, repetitive metabolic
imaging in humans, which may be an important tool in the development of drugs targeting BAT.
Given the relative ease of implementation in a clinical setting and the range of available
H-labeled substrates, DMI has the potential to become a widespread MRI modality for metabolic
imaging in general.
