GLP-1 receptor expression and beta-cell mass in patients with type 2 diabetes

Reliable imaging biomarkers for non-invasive characterisation of beta cell mass
are needed to aid our understanding regarding the relationship between
beta-cell mass and function during the course of type 2 diabetes (T2D). This
study will provide critical information necessary to validate the applicability
of exendin-based imaging techniques in patients with T2D. The characterization
of beta-cells is currently limited to pancreatic specimens available at
autopsy, as in vivo pancreatic biopsy is associated with complications
unacceptable in clinical studies [1]. To date, only measurements of circulating
C-peptide and insulin levels can be obtained, but these measures do not reflect
beta-cell mass, only total beta-cell function. Reliable imaging biomarkers for
non-invasive characterisation of beta cell mass are therefore needed. These
biomarkers could also be used to validate novel therapeutic strategies aimed to
increase or preserve BCM or identify whether patients are eligible for a
certain therapeutic strategy (e.g. when certain amount of beta-cells is
required). One can also think of identifying responders to therapies early to
avoid unnecessary drug use and the accompanying costs.

We aim to determine the specificity of radiolabelled exendin during the course
of T2D and to examine the role of glycemic control on the correlation between
pancreatic 111In-exendin uptake, BCM and GLP-1R expression in patients with T2D
undergoing (partial) pancreatectomy. This will not only allow us to establish
definite proof regarding the role of glycemic control on exendin uptake in
humans, but also to establish clinical guidelines for the interpretation of
clinical exendin-based scans in patients with T2D to avoid false interpretation
of the scans.

After recruitment of the participating individuals, patients will undergo an
enrollment check consisting of a medical interview and a physical examination
performed by a qualified physician (in case this is not done during intake and
surgical evaluation for pancreatectomy). Recent blood samples for standard
laboratory checks (blood counts, electrolytes, liver enzymes, inflammation
parameters) that have been taken in the preparation for pancreatectomy, will be
used. To obtain information about glycemic control, patients will receive a
glucose sensor subcutaneously (plaster with a small needle) to monitor glucose
profiles continuously for maximally 7 days. If the physical status of the
patient is good enough, an arginine stimulation test will be performed to
assess beta-cell function. Prior to pancreatectomy, patients will be injected
with either 111In-exendin (16h before before surgery) or 800CW-exendin (16h
before surgery).
After pancreatectomy, samples for histology, autoradiography, and gene
expression profiling, will be taken from the pancreatic head, body and tail and
duodenum/pylorus if resected. If possible, subcutaneous and visceral adipose
tissue samples will be obtained from the abdominal wall and the omentum), as
the abdominal wall and omental bursa will already be opened during this
surgery.

All individuals will undergo physical examination and blood sampling for
standard laboratory parameters and they will receive a glucose sensor
subcutaneously (small band-aid with a small needle) to monitor glucose profiles
continuously. This will require a single and rapid placement of the sensor,
which includes placing a small needle in the subcutis. The sensor will remain
in place for a period of 7 days.
If the physical status of the patient is good, patients will undergo an
arginine stimulation test. This test is performed in the morning and is
preceded by an overnight 12-hour fast, during which water may be drunk. For
this test blood sampling is done via a venous catheter.
The injection of exendin may result in nausea and headache as has been reported
for (much higher doses of) Byetta® in therapy studies. Also in our study
monitoring beta-cell grafts in T1D patients (NL52630.091.15), two patients
experienced nausea and had to vomit. These patients used Byetta in high doses
in the past, which might explain their sensitivity to the compound.
In addition, single cases of low blood pressure and low blood glucose levels
have been described previously after accidental heavy overdosing of Byetta®.
However, in our previous studies with 111In-DTPA-[K40]-Exendin-4 (CPOP-EX and
GLP1-EX-GELO) we did not observe any side effects.
The expected radiation exposure will not exceed 10 mSv and is therefore
considered minimal to little. The envisaged clinical endpoint of this project
is the full validation of GLP-1R imaging for BCM quantification in patients
with T2D and to deliver protocols/guidelines regarding the interpretation of
clinical exendin scans in patients with metabolic stress. As beta-cell
dysfunction, dedifferentiation and death are presumed to be central events in
the pathogenesis of both type 2 and type 1 diabetes, this imaging platform can
help to elucidate the fate of beta-cells during the development and progression
of type 2 and type 1 diabetes.