Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03182296 |
| Other study ID # |
NL56938.091.16 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 10, 2016 |
| Est. completion date |
January 1, 2026 |
Study information
| Verified date |
January 2024 |
| Source |
Radboud University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In order to evaluate the difference in beta cell mass in women with and without a history of
gestational diabetes mellitus (GDM), investigators aim to compare quantitative PET imaging of
the pancreas between these groups. Investigators propose to measure uptake of
68Ga-NODAGA-exendin-4 in the pancreatic beta cells of these women as a measure for beta cell
mass. Furthermore, investigators aim to compare uptake of the radiolabeled tracer to beta
cell function measured by laboratory parameters. These highly relevant data within this
at-risk population for type 2 diabetes (T2D) will provide the investigators with more
information on the role of beta cell mass in the predisposition for development of T2D
leading to better knowledge on the pathophysiology of this disease. This could be of great
interest for development of new treatment options.
Description:
Gestational diabetes Insulin is produced by pancreatic beta cells and is needed for optimal
glucose homeostasis. In healthy individuals, the mass and function of beta cells changes to
adapt to variations in insulin demand in the body. For example, adaptive beta cell
hyperplasia, hypertrophy and hyperfunction occur in situations of increased metabolic demand,
like pregnancy.
In rodents a 2-3 fold increase in beta cell mass is observed at the end of gestation. By the
time of delivery, beta cell function as well as beta cell mass return to normal levels.
Although to a lesser extent than in rodents, also in humans there have been studies
indicating that the beta cell mass may increase during pregnancy and return to normal in the
postpartum stage.
When there is no sufficient compensation during pregnancy due to failure in beta cell
expansion or function, gestational diabetes mellitus (GDM) occurs.
GDM complicates 2-5% of pregnancies in Caucasian women and is characterized by glucose
intolerance with the onset or first diagnosis during pregnancy. GDM can have serious
consequences for both the child as well as the mother. Risks to the child include fetal
macrosomia as well as long-term health consequences like obesity, hypertension, dyslipidemia,
glucose intolerance and type 2 diabetes (T2D). Maternal risks include an increased
probability of caesarean delivery accompanied by an increased risk of maternal morbidity.
In women with GDM, glucose homeostasis is returned to normal levels shortly after delivery.
However, women with a single gestational diabetes pregnancy present with faster deterioration
in insulin sensitivity and beta cell compensation compared to women without a history of
gestational diabetes. These women therefore have a 7-fold increased risk of developing T2D in
the future. Furthermore, women with a history of GDM have a 10-fold increased risk of
developing GDM in future pregnancies.
GDM and T2D The prevalence of T2D in the Netherlands is 600.000-800.000 and each year ~70.000
new patients are diagnosed. Patients with T2D have a 2-4 times increased risk of developing
cardiovascular disease. These complications seriously decrease the quality of life and life
expectancy of T2D patients. The burden of this disease not only affects these patients but
our society as well. Health care costs with respect to diabetes amounted to 814 million euro
in 2005 in the Netherlands and indirect costs because of absence of work are unknown but
thought to be substantial.
T2D is mainly characterized by defective insulin secretion and peripheral insulin resistance.
It develops chronically over years to decades before it becomes apparent. Early in the
disease progression, pancreatic beta cells respond to initial insulin resistance by
increasing insulin secretion to preserve a near-normal glucose level. Over time the beta cell
mass reduces gradually, leading to a decline in insulin secretion causing hyperglycemia. Beta
cell failure is dependent on several factors like genetic predisposition, poor dietary
control, glucotoxicity and lipotoxicity, liver steatosis and therapy itself.
In the process of development of disease many secondary changes in metabolism, hormonal
signaling and body composition occur which are difficult to discriminate from those that
initially started the pathophysiological process. Therefore, the early pathogenesis of T2D is
still not completely understood. Risk factors for the development of T2D overlap with the
risk factors for GDM. These common risk factors suggest an overlapping cause of the disease.
In patients with GDM glucose homeostasis cannot be maintained under conditions of increased
metabolic demand. This fact, together with the increased risk of developing T2D in the future
suggests a specific predisposition for beta cell dysfunction in these patients.
Beta cell mass in T2D Besides the well-known role of peripheral insulin resistance in the
early pathogenesis of T2D, there is also evidence suggesting the importance of beta cell
mass. Studies performed on autopsy material of T2D patients in various populations show a
significantly reduced beta cell mass. This reduction could be explained by accelerated beta
cell death in these patients. A genetic difference in beta cell mass could however also play
a role. Large variations in fractional beta cell area have been shown between individuals in
the pre- and postnatal growth period. Furthermore, a recent study by Brom et al. suggests
that there is a large variation in beta cell mass between individuals. In this study beta
cell mass was measured non-invasively in healthy subjects as well as type 1 diabetic patients
by 111In-exendin-4 SPECT/CT. While the beta cell mass in these diabetic patients was found to
be significantly lower than in healthy subjects, a wide range in beta cell mass was found in
both groups. These results are in line with an earlier study where wide ranges in beta cell
mass were found in pancreas obtained at autopsy of diabetic and non-diabetic subjects.
An initial deficit in beta cell mass could thus play a key role in the development of T2D.
Patients with a history of GDM have a significantly increased risk of developing T2D. While
an increase in beta cell mass has been found in healthy women during pregnancy, it is not yet
known whether patients with GDM have a deficit in beta cell mass. While little is known about
beta cell mass in women with a history of GDM, it is well recognized that these women have a
chronic defect in beta cell function that progressively worsens in the years after the
pregnancy and mediates their high risk of progression to T2D. This deterioration of beta cell
function begins as early as the first year after delivery, is partly driven by hepatic
insulin resistance, takes place in the presence of initial normal glucose tolerance, and
precedes the development of abnormal glucose tolerance. Accordingly, women with a recent
history of GDM represent a patient population in which there is beta cell dysfunction without
the potential confounding effect of hyperglycemia (and resultant glucotoxicity).
Evaluation of beta cell mass in women with a history of GDM could thus be very beneficial for
our understanding of the role of beta cell mass in the development of T2D. It would be of
great interest to examine whether the population of women with a history of gestational
diabetes, who have a significantly increased risk of developing T2D, have a lower mean beta
cell mass compared to the population of women without a history of gestational diabetes.
Also for the development of new treatment options for T2D, more knowledge on the role of beta
cell loss in the development of T2D would be beneficial. While current and new anti-diabetic
drugs are mainly targeting insulin secretion and action or glucose uptake, evidence from
animal experiments suggests the feasibility of regulating beta cell mass.
Imaging of beta cells in vivo Reliable, sensitive and specific visualization of living
pancreatic beta cells in vivo is important to broaden the understanding of the role of beta
cell mass in the onset and development of T2D. This could benefit further research in the
causes of beta cell failure in T2D and therapeutic options to delay progressive loss of beta
cells. Because of the multifactorial nature of T2D disease, defining a study population for
assessment of beta cell mass is difficult. Patients with a history of GDM would be a very
attractive population to study in this context as an at-risk cohort for T2D. These patients
have a clear predisposition for development of T2D evidenced by their increased risk for
developing this disease and the faster deterioration of insulin sensitivity and beta cell
compensation.
GLP-1 receptor imaging by PET For specific non-invasive imaging of beta cells, investigators
have developed a highly beta cell-specific radiolabeled exendin-based GLP-1 (glucagon-like
peptide-1) analog which, after radiolabeling, can non-invasively be detected in the human
body. GLP-1 is an incretin hormone that specifically binds to beta cells and is responsible
for post-prandial insulin-secretion. Its specificity for beta cells has been shown and a
linear correlation of the beta cell mass and the signal obtained with this tracer has been
established in rats.
GLP-1R imaging has been shown to be suitable for imaging of insulin producing pancreatic
neuroendocrine tumours (IPPNET). Furthermore, the feasibility of visualization of
transplanted beta cells with GLP-1R imaging has been shown by imaging of autologous islets
transplanted into muscle.
