Comparison of the beta cell mass during and shortly after the honeymoon phase of type 1 diabetes using Ga-68-exendin PET

The exact role of beta cell mass during the development and course of diabetes
is still poorly understood. Initially, the belief was that practically all beta
cells would die after the previously described autoimmune attack in type 1
diabetes (T1D). However, recent literature suggests that a considerable number
of beta cells can survive this autoimmune attack, even when their function
gradually dissipates. This could mean that the function of the surviving beta
cells is partially or completely lost. The contradiction between the initial
belief and recent literature indicates the still consisting lack of knowledge
concerning beta cell mass, function and their relation. Therefore, further
research on beta cell mass is essential to obtain more insights that might aid
in the development of novel therapies for diabetes.
We want to focus on a specific phase of T1D that is called the 'honeymoon
phase' or period of partial remission. Once insulin treatment has started, the
honeymoon phase will arise in most patients. In this period, T1D patients
become temporarily less insulin-dependent due to an increase of endogenous
insulin secretion and improvement of peripheral insulin sensitivity. The
occurrence and duration of the honeymoon phase might differ depending on
factors such as the age at onset and manifestation of T1D. Unfortunately, the
honeymoon phase is only temporary, in which a decline in blood glucose
regulation will be seen afterwards, leading to an increasing demand for
insulin. During the honeymoon phase, the decrease in insulin dependence
suggests the presence of beta cells, indicating that this change in metabolic
control depends on the cell function. However, after the honeymoon phase, it is
not completely clear whether the ongoing deterioration of glycemic control can
be attributed to the loss of beta cell function or to a decreasing number of
beta cells (beta cell mass). To increase understanding of this change in
metabolic control after the honeymoon phase, we want to perform repeated
measurements of the beta cell mass and function, during and shortly after the
honeymoon phase.
The aim of this study is to compare beta cell mass and function during and
shortly after the honeymoon phase. Beta cell mass will be determined using
Ga-68-exendin positron emission tomography (PET), which allows visualization
and absolute quantification of tracer uptake, providing a non-invasive method
to measure pancreatic beta cell mass. In addition, the beta cell function will
be determined by a mixed-meal tolerance test. The comparison of both
measurements can lead to an increased understanding whether changes in insulin
demand after the honeymoon phase is mainly dependent on a decline in the beta
cell mass, or because of a decrease in functional beta cells (ratio functional
and non-functional beta cells and insulin secretory capacity per beta cell).
The outcome of this study can provide new insights, which can contribute to the
development of novel treatment options, aimed at preservation and stimulation
of residual beta cells to eventually lower the impact of diabetes on the life
of patients.

The study objective is to measure beta cell mass and function in subjects with
type 1 diabetes during and shortly after the honeymoon phase, to determine
whether the change in metabolic control is mainly caused by a decrease in the
total number of beta cells or more dependent on the function of the beta cells.

Subjects in the honeymoon phase of T1D will be recruited from the outpatient
clinic of the Department of Paediatrics and Internal Medicine of the Radboudumc
and from Diabeter in Rotterdam (centre for paediatric and adolescent diabetes
care and research). The subjects must have a minimum age of 16 years and will
be asked by their physician for participation, at least 3 weeks after
diagnosis. In case patients agree to participation, the researcher will
approach them to provide further information regarding the study.
After recruitment, subjects will visit the Department of Radiology and Nuclear
Medicine in the Radboud University Medical Center (Radboudumc) in Nijmegen or
Diabeter in Rotterdam. During this first visit, a glucose sensor will be placed
to obtain glucose profiles via continuous glucose monitoring (CGM), providing
valuable insights into their metabolic control. CGM requires the placement of a
blinded sensor that measures glucose subcutaneously.
During the second visit, a medical check will be performed by a qualified
physician. This medical check will include a medical interview and a physical
examination. Blood samples will be taken to obtain laboratory values of the
pancreas, kidney and liver function (C-peptide, insulin, glucose, HbA1c,
creatinine, ALAT, ASAT). The beta cell function will be determined by a
mixed-meal tolerance test.
During the third visit, which will take place at the Department of Radiology
and Nuclear Medicine, a PET/CT scan will be made. For this, 0.75 MBq/kg of
Ga-68-NODAGA-exendin-4 will be administered to the study participant, which is
preceded by a fasting period of 4 hours. The PET/CT scan will take place at the
start of the tracer injection.
Once the honeymoon phase has passed, the subjects will visit the Department of
Radiology and Nuclear Medicine or Diabeter again for a fourth visit, to perform
CGM for a second time. A fifth visit is needed to perform a second mixed-meal
tolerance test. Lastly, the sixth and last visit is required at the Department
of Radiology and Nuclear Medicine to repeat the PET/CT scan.
Image analysis and statistical analysis will be performed at the Department of
Radiology and Nuclear Medicine.

The study requires 6 visits in total. The participants will need to visit the
Department of Radiology and Nuclear Medicine of the Radboudumc in Nijmegen or
Diabeter in Rotterdam twice for the placement of the glucose sensor for CGM.
This will require a single and rapid placement of the blinded sensor, which
includes placing a small needle in the subcutis. The advantages of CGM are the
reduction in fingerpricks in comparison to 7-points curves and the increased
number of glucose measurements that can be performed.
A mixed-meal tolerance test will be performed . For the PET/CT scans, two
additional visits at the Department of Radiology and Nuclear Medicine in the
Radboudumc are required. During all 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 intravenous
catheters, there is a small chance of bruising, pain and inflammation at the
site of catheter placement.
For the PET/CT scan, 0.75 MBq/kg 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. In imaging studies this has only been observed in 2 cases so far (see
section 5.4). 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
this study, we will only administer 0.75 MBq/kg Ga-68-NODAGA-exendin-4.
Therefore, no (serious) adverse events will be expected. In case of
administering Ga-68-NODAGA-exendin-4, the expected radiation exposure will be
0.023 mSv/MBq. In addition, 1.25 to 2 mSv will be received due to the low-dose
CT. The expected radiation doses will vary for each subject, noting that the
injected dose is based on the body weight of the participant. The comparison of
the beta cell mass during and shortly after the honeymoon phase is possible,
requiring 2 PET/CT scans per subject. The total expected radiation exposures
are listed in section 5.9 (table 2 and 3). The level of radiation exposure can
therefore be considered minor to intermediate according to the ICRP.
Despite the radiation exposure, Ga-68-exendin PET can be used to provide in
vivo visualization and quantification of the beta cell mass in a longitudinal
manner. Beta cell mass measurements in humans are needed, especially
considering the lack of knowledge regarding the changing aspect of beta cell
mass. The added clinical value of this study is to improve understanding of the
decline in beta cell function after the honeymoon phase and might provide new
insights in the field of diabetes.
The participants will not benefit directly from this study.