Development of deuterium metabolic imaging to map body biochemistry with MRI

In type 2 diabetes, both carbohydrate and lipid metabolism in the liver are
dysregulated, which is strongly related with hepatic insulin resistance.
However, our knowledge of the exact disturbances in the metabolic pathways in
the insulin resistant liver is limited due to the fact that sensitive, direct
measurement methods are currently lacking. The aim of this project is to
develop a completely novel and non-invasive method to measure hepatic
carbohydrate and lipid metabolism directly inside the liver in humans. The
method is based on deuterium metabolic imaging (DMI) combined with
administration of deuterated compounds. We expect that DMI has sufficient
sensitivity to dynamically probe metabolic pathways in the human liver in 3D
imaging mode.

Primary objective: Develop a completely novel and non-invasive method to map
body metabolism in humans based on DMI on a 7T MRI scanner.
Secondary objectives: To demonstrate proof of concept by measuring (1) hepatic
glucose metabolism and (2) de novo
lipogenesis in the liver using DMI, in healthy volunteers and patients with
type 2 diabetes.

Two feasibility studies will be carried out to measure (1) hepatic glucose
metabolism and (2) de novo lipogenesis in the
liver using DMI, in healthy volunteers and patients with type 2 diabetes.

Subjects participating in study 1 will visit the UMC Utrecht once. After an
overnight fast, subjects will get an MRI scan which takes approximately 120
min. Before or during the scan, they will receive an oral dose of deuterated
glucose (maximum 0.75 g/kg body weight) dissolved in water. The glucose
solution can be consumed slowly (in 5-10 min).To avoid multiple vena punctures
and to be able to collect blood samples during the MRI, an intravenous access
site will be installed in a vein in the arm to collect blood samples. A blood
sample of 20 ml will be collected before the oral glucose dose, and 12 small
blood samples of 3 ml will be collected during the 120 min after the oral
glucose dose.
Subjects participating in study 2 will visit the UMC Utrecht twice. On day 1,
subjects will undergo a baseline 7T MRI scan at the 7T MRI scanner (in the fed
state), which will take approximately 60 min. After the scan, volunteers will
receive an initial bolus of heavy water of 3.5 ml/kg body water. From day 2
until day 5, volunteers will consume a maintenance dose of heavy water of 1.25
ml/kg body water. On day 5, subjects will get another 7T MRI scan, which will
take approximately 60 min. Blood samples of 20 ml will be collected on day 1
before the bolus administration of heavy water, and on day 5 before the MRI
scan.
The intake of above mentioned amounts of deuterated glucose and heavy water,
and drawing of the above mentioned amount of blood does not affect the health
of participants. Deuterium (2H) is a stable, non-radioactive, isotope of
hydrogen, and biologically, deuterated glucose and heavy water behave similarly
to normal glucose and normal water, respectively. No adverse effects have been
observed with oral administration of deuterated glucose at the dosage which
will be used in this study. When body water deuterium enrichment reaches 3%,
subjects can experience dizziness and/or nausea, because it affects the density
of the fluid in the inner ear, but this effect is only temporary (disappears
within a few hours) and no long-term adverse effects have been reported. The
bolus of heavy water will therefore be consumed in small portions during the
day and this will take place in the UMC Utrecht under supervision of medical
staff. MRI is a safe and reliable technique for subjects without
contra-indications for undergoing MRI and is widely used in clinical
examinations and scientific research. Subjects included in the study will have
no contra-indications for MRI and they will be screened again for
contra-indications before undergoing the MRI examination(s). To ensure
technical feasibility, the MRI protocol will behas been extensively
pilot-tested in healthy subjects at natural abundance according to
METC-protocol number 15-466, showing good sensitivity and stability of the 3D
DMI measurements.
To our knowledge, there is no risk of participation in this study other than
the small risk associated with venipuncture.