Visualizing beta cells after Intrahepatic Islet of Langerhans Transplantation

Detecting damage to islets with a reliable imaging technique could be important
for improving islet survival after transplantation. This could lead to better
patient outcomes which would be of great interest for the treatment of type 1
diabetes. In order to assess the possibility of visualizing transplanted islet
grafts with 68Ga-NODAGA-exendin-4 PET, we aim to perform a proof-of -concept
study in 10 patients with type 1 diabetes who have undergone intrahepatic islet
transplantation with biochemically proven functional islet grafts and 5
patients with T1D who are on the waiting list for islet transplantation. We
propose to determine the uptake of the radiolabeled tracer and compare it to
functionality of the islet grafts. Furthermore, we aim to evaluate the
distribution of the transplanted islets in the liver and correlate this with
structural hepatic abnormalities such as steatosis. These highly relevant data
will provide us with more information on the suitability of GLP-1 receptor
imaging for monitoring of transplanted islet mass.

Primary Objective:
Compare the uptake of 68Ga-NODAGA-exendin-4 in the liver between T1D patients
with functional islet grafts (C-peptide > 0.8 nmol/L after mixed meal
stimulation test and relevant laboratory parameters as HbA1C and exogenous
insulin administration) and healthy volunteers using PET.

Secondary Objective(s):
The secondary objectives are:
- Comparing the uptake in the liver to islet graft function, defined by
clinical parameters (C-peptide levels after mixed meal stimulation test, HbA1c
levels and exogenous insulin usage).
- Assessing distribution of uptake across the liver (PET) reflecting islet
distribution.
- Correlate the distribution of uptake in the liver (PET) with structural
hepatic abnormalities, such as hepatic steatosis (MRI/MRS)
.

Proof-of-concept study in which we will compare the uptake of
68Ga-NODAGA-exendin-4 in the liver of 10 patients with intrahepatic islet
transplantation with the uptake in the liver of 5 healthy volunteers and
correlate the distrubution of uptake with graft performance and structural
hepatic abnormalities (as determined with MRI).

All individuals will undergo physical examination and blood sampling for
laboratory parameters (first visit). In addition, all patients with islet
grafts will undergo a mixed meal tolerance test. At the second visit
68Ga-NODAGA-exendin-4 will be administered intravenously and dynamic scanning
with breath gating will be performed for 60 minutes at a single bed-position.
After this a static scan of 20 minutes will be made. After injection of the
radiopharmaceutical, blood samples will be drawn from an intravenous catheter
for determination of blood glucose levels. Also, blood pressure will be
measured. Injection of the radiopharmaceutical may theoretically result in
nausea and headache as has been reported for (much higher doses) of Byetta® in
therapy studies. In addition, single cases of low blood pressure and low blood
glucose levels have been described after accidental heavy overdosing of
Byetta®. Therefore, participants will be closely monitored. However, in another
study (CPOP-EX), we did not observe any side or adverse effects after
111In-DTPA-[K40]-Exendin 4 injection for all 20 patients included. After the
PET/CT a MRI will be performed to visualize hepatic abnormalities (MRS spectra
will be obtained to identify hepatic steatosis) and this will take about 45
minutes.
The expected radiation exposure is 5.5 mSv and is therefore considered minimal
to little. However, if the technology would indeed allow visualization of the
transplanted islets, the impact on optimizing islet transplantation and thereby
diabetes treatment and potential cure of the disease would be very high.