Beta cell imaging in type 1 diabetes with stable near-normal and unstable glucose control using PET

The change in beta cell mass in type 1 diabetes (T1D) is still poorly
understood. Initially, the belief was that this could be explained by the loss
of all pancreatic beta cells due to the autoimmune attack. However, recent
literature suggests that a considerable number of beta cells can survive this
attack. This could mean that certain beta cells survived, but have lost their
function. The ratio of functional and non-functional residual beta cells might
play an important role in the degree of glycemic control. It would therefore be
of great interest to study residual beta cell mass in two types of T1D patients
that differ in glycemic control. Although both types of patients receive
treatment, one group of patients is characterized by a stable near-normal
glucose control (control group) while the second group is characterized by an
unstable glucose control. These groups will be defined based on their HbA1c
values, number of severe hypoglycemic events and hypoglycemic awareness. In
case glycemic control mostly depends on beta cell function and less on beta
cell mass, novel therapies could focus on the functional reactivation of these
non-functional beta cells to restore overall beta cell function. This could
especially be in favour of patients with an unstable glucose control. Beta cell
mass will be determined using Ga-68-NODAGA-exendin-4 positron emission
tomography (PET), which allows visualization of pancreatic beta cells as well
as absolute quantification of tracer uptake, providing a measure for the
pancreatic beta cell mass. The outcome of this study will lead to a better
understanding of the relation between the amount of residual beta cells, beta
cell function and the influence of glycemic control. This could provide new
insights regarding the development of new therapies to improve beta cell
function and glycemic control, which could lower disease burden and improve the
patient*s quality of life.

The main study objective is to measure residual beta cell mass, indicated by
the pancreatic uptake of Ga-68-exendin using quantitative PET, in type 1
diabetes patients with stable near-normal and unstable glucose control, to
improve understanding of the relation between residual beta cell mass and
glycemic control.

T1D patients with stable near-normal and unstable glucose control will be
recruited from the outpatient diabetes clinic of the Radboudumc in
collaboration with the Department of Internal Medicine. Advertisements will be
placed on the websites and social media (e.g. Twitter/Facebook) of the
Radboudumc and diabetes-gerelateerde websites (Diabetes Fonds, eendiabetes,
diabetestype1) for additional recruitment.
Subsequent to patient recruitment, a medical check will be performed at the
Department of Radiology and Nuclear Medicine in the Radboudumc by a qualified
physician. This medical check includes a medical interview and a physical
examination. Blood samples will be taken to determine different laboratory
parameters (C-peptide, insulin, glucose, HbA1c, creatinine, ALAT, ASAT). In
addition, 2 blood samples will be taken and processed for phenotyping. The beta
cell function will be determined by a mixed-meal tolerance test.
During the second visit at the Department of Radiology and Nuclear Medicine a
PET/CT scan will be made. After a fasting period of 4 hours, 75 MBq of
Ga-68-NODAGA-exendin-4 will be administered. The PET/CT scan will be performed
1 hour after administration. For a period of 7 days (prior to the scan) glucose
profiles will be obtained by continuous glucose monitoring. This requires a
single placement of a sensor that measures glucose subcutaneously. These
profiles will give detailed information on the course of blood glucose levels
of each subject and will provide insight into their metabolic control, which
will be valuable for this study.

The participants need to visit the Department of Radiology and Nuclear Medicine
twice. During both visits blood sampling will be performed. Blood sampling will
be done via an intravenous catheter, which reduces the number of required
venipunctures. Due to the placement of an intravenous catheter, there is a
small chance of bruising, pain and inflammation at the site of catheter
placement. During the second visit a single dose of 75 MBq
Ga-68-NODAGA-exendin-4 will be administered. Injection of this
radiopharmaceutical may theoretically result in nausea and headache as has been
reported for (much higher doses) of Byetta® in therapy studies, although this
has never been observed in imaging studies so far (see section 5.4 in reseach
protocol). In addition, single cases of low blood pressure and low blood
glucose levels have been described after application of therapeutic or higher
doses of Byetta®. Although low blood glucose levels only occurred after
accidental heavy overdosing of Byetta®, patients will be closely monitored. In
the period between the two visits, glucose levels will be measured
subcutaneously through continuous glucose monitoring. This requires the single
placement of a subcutaneous sensor (frequently used by diabetes patients).
Subjects are not hindered by the sensor in terms of showering, swimming, et
cetera.
In this study, we will only administer 75 MBq Ga-68-NODAGA-exendin-4 and
therefore no (serious) adverse events will be expected. In case of
administering 75 MBq Ga-68-NODAGA-exendin-4 followed by a PET/CT scan, the
expected radiation exposure will be 3.7 mSv. The radiation exposure can
therefore be considered minimal to little. Despite a low radiation exposure is
needed, Ga-68-exendin PET provides a sensitive and specific visualization of
the beta cell mass in vivo and allows accurate quantification of the beta cell
mass, which is beneficial to improve understanding of the pathophysiology of
T1D. The added clinical value of this method is that beta cell imaging using
Ga-68-exendin PET, can be applied to select specific patients for future
treatment options.
The participants will not benefit directly from this study.