Nano-MRI to visualize pancreatic inflammation in individuals with recent-onset type 1 diabetes

In this project we propose to use Ferrotran-enhanced MR imaging (nano-MRI)
using ultra-small superparamagnetic nano-iron oxide particles (Ferrotran:
ferumoxtran-10 Lyophilisate) as a contrast agent to visualize both endocrine
and exocrine pancreatic inflammation in early-onset type 1 diabetes (T1D).
Reliable visualization and quantification of inflammation in the pancreatic
islets and the exocrine pancreas will provide important information on the
inflammatory processes involved in the early development of T1D. Furthermore,
it could represent an early marker for monitoring of disease progression and
response monitoring of anti-inflammatory therapies.

The primary objective is to compare pancreatic macrophage infiltration between
individuals with T1D and controls by imaging intracellular iron particle
accumulation in macrophages by late-phase MR imaging. To achieve this we will
first develop an optimized nano-MRI protocol in 5 healthy volunteers.

We aim to perform an observational clinical trial in which we will include 10
individuals with recent-onset T1D and 10 healthy control subjects. We will
assess pancreatic perfusion by MR imaging after infusion of Ferrotran in the
angiographic phase before and after stimulation of the pancreatic beta cells
with glucose. Also, we will assess uptake of the iron particles in infiltrating
macrophages by performing MR imaging in the lymphotrophic phase. Furthermore,
we aim to cross-validate this technique by comparing the results to
quantitative dynamic [18F]FDG PET/CT imaging, an established method to
visualize inflammation.

Intravenous injection of Ferrotran and 18F-FDG

All individuals will undergo blood sampling for specific laboratory parameters.
In addition, all participants in the second phase of the trial will undergo an
oral glucose tolerance test (first visit). At the second visit, Ferrotran
Lyophilisate will be administered intravenously. Subsequently (for participants
in the second phase of the trial), [18F]FDG will be administered intravenously
and dynamic PET scanning will be performed for 1 hour starting at the time of
injection of the tracer. At the third visit, 2 MR acquisitions (lymphotrophic
and angiotrophic phase) will be performed. Subsequently, 0.33 g/kg glucose will
be administered intravenously over 1 minute. After this, 1 additional MR
acquisition of the angiotrophic phase will be performed.

There are some risks associated with administration of Ferrotran Lyophilisate.
Ferrotran Lyophilisate was administered to 1,663 adult subjects in phase I to
III studies. About 18.2% of subjects experienced at least one adverse reaction.
These reactions were not dose-dependent but partially related to the infusion
speed * by fast intravenous infusion the risk of side effects was higher. The
most frequently reported adverse reactions were back pain, headache and
hypersensitivity symptoms. Most adverse reactions were mild to moderate, short
(75% occurred within and lasted less than one hour after the start of the
infusion), and had a favorable outcome. Some delayed adverse reactions (up to
several days after the start of the infusion) have been reported.
Serious potentially allergic reactions have been uncommonly (0.4%) observed
during clinical studies of Ferrotran Lyophilisate. These types of reactions,
which included anaphylactic shock, may very rarely be life- threatening or
fatal. They can occur irrespectively of the dose of Ferrotran Lyophilisate
administered.

Participants do not personally benefit from participation in the study.

The study could have a large impact on research into the pathophysiology of
T1D. Currently, diagnosis of T1D as well as monitoring of disease progression
is based on plasma markers like glucose and C-peptide combined with the
presence of auto-antigens. Plasma markers are late markers, which usually lead
to diagnosis when significant beta cell loss has already occurred. Also,
auto-antibodies are persistent and do not reflect the inflammatory status at a
specific time. This is limiting for research into new therapeutic options and
the possibility of disease prevention.
By visualizing pancreatic inflammation with nano-MRI, individuals with T1D
could be diagnosed early in the disease process, before significant beta cell
loss has occurred. This will facilitate screening individuals in high-risk
populations. Furthermore, the development of the disease can be followed
closely, enabling reliable staging of the disease and monitoring of therapeutic
interventions. In addition to disease staging and monitoring, nano-MRI will
provide crucial information on the genesis, early development and progression
of T1D. Nano-MRI could give new insights into the specific inflammatory
processes, that play a role in the development of T1D. Also, in combination
with beta cell imaging, which is performed at the Radboudumc in Nijmegen using
[68Ga]exendin PET/CT, the extent to which pancreatic inflammation correlated
with beta cell destruction could be determined. This increase in knowledge will
be of great value for research into future therapeutic options and possible
prevention of the disease.