Current Medicinal Chemistry–Immunology, Endocrine & Metabolic Agents Volume 4, No. 4, 2004
Contents
Imaging
Diabetic Pancreas
Guest
Editor: Anna Moore
Why Image the Pancreatic Beta Cell? Pp.251-252
Maren
R. Laughlin
Optical Imaging Agents and Potential Application
in the Assessment of Pancreatic Beta Cells Pp.253-269
Samuel
Achilefu
Potential Approaches for Beta Cell Imaging
with PET and SPECT Pp.271-280
C.-Y.
Shiue, A. Schmitz, R. Schirrmacher, G. G. Shiue and A. Alavi
Imaging of Pancreatic Beta-Cell
Signal-Transduction Pp.281-299
Martin
Kohler, Daniel Nyqvist, Tilo Moede, Helene Wahlstedt,Over Cabrera, Ingo
Leibiger and Per-Olof Berggren
Bioluminescence Imaging of Pancreatic Islet
Transplants Pp.301-308
Xiaojuan
Chen and Dixon B. Kaufman
Antibodies to Islet Beta Cell Surface Markers
Pp.309-313
Ole
D. Madsen and Klaus H. Kaestner
Approaches for Imaging the Diabetic Pancreas:
First Results Pp.315-331
Anna
Moore and Zdravka Medarova
Imaging Metabolic and Signaling Targets in
the Pancreatic Beta Cell Pp.333-337
Louis
H. Philipson and Michael Wm. Roe
In Vivo Bioluminescence Imaging to Assess Pancreatic
Islets Pp.339-347
Alvin
C. Powers and E. Duco Jansen
Toward the Design of MR Agents for Imaging b-Cell Function Pp.349-369
Mark
Woods, Shanrong Zhang and A. Dean Sherry
Abstracts
[Back to top] Why Image the Pancreatic Beta Cell?
Maren
R. Laughlin
[Back to top] Optical Imaging Agents and Potential
Application in the Assessment of Pancreatic Beta Cells
Samuel
Achilefu
Diseases of the
pancreas are life-threatening because of its central role in glucose
homeostasis and digestion. Regulation of blood glucose falls within the purview
of pancreatic beta cells, whose primary role is to produce insulin.
Malfunctioning of beta cells can lead to diabetes, the severity of which has
been shown to correlate with pancreatic beta cell mass (PBCM). Consequently,
methods that can image PBCM would play a major role in the management of type 1
diabetes. To be successful, such imaging methods must be highly sensitive and
specific because of the anatomical challenges and the small size of the
pancreas. The desired sensitivity and specificity can be obtained in
conjunction with molecular contrast effectors to decipher pathologic from
normal tissues. Because of its high sensitivity, nuclear methods have been the
dominant molecular imaging method for human applications. For this reason, a
variety of radiopharmaceuticals has been developed. To minimize the exposure of
patients to radioactivity, optical imaging is a complementary and viable
alternative to nuclear methods. Optical methods are highly sensitive and use
non-ionizing radiation to interrogate the molecular basis of pathogenesis. This
review will focus on the development of molecular beacons and their potential
application in the imaging of pancreatic beta cells. It is most likely that contrast-mediated
optical imaging of pancreatic islet cells will combine molecular specificity
with high sensitivity to furnish useful diagnostic and prognostic information
by endoscopic methods. Alternatively, minimally invasive continuous organ
function monitoring methods could be developed to assess indirectly the
functional status of pancreatic beta cells by optical spectroscopy.
[Back to top] Potential Approaches for Beta Cell Imaging
with PET and SPECT
C.-Y.
Shiue, A. Schmitz, R. Schirrmacher, G. G. Shiue and A. Alavi
Diabetes mellitus is a
major public health problem and comprises a heterogeneous group of disorders
characterized by high blood glucose levels. Two major types of diabetes
mellitus have been defined: type 1 and type 2. Pancreatic beta-cell mass (BCM)
is markedly reduced in type 1 diabetes due to selective autoimmune destruction
of insulin-producing beta-cells of the pancreas. To date, the accurate
assessment of pancreatic beta-cells in human diabetes has been limited to
autopsy studies, which usually suffer from inadequate clinical information.
Thus, the development of noninvasive technique to assess the state of viability
of beta-cells in vivo during the silent phase of prediabetes or after
islet transplantation will be useful for clinical intervention. A number of
imaging modalities have been proposed to evaluate BCM including cellular
imaging, MRI, and nuclear imaging. However, none of these modalities has yet
been successfully applied to human studies. In this article, we review the
development and the feasibility of using radiolabeled metals, monoclonal
antibody, monosaccharides, sulfonylurea receptor ligands and gene expression
reporter probes as radiotracers for imaging BCM with PET and SPECT.
[Back to top] Imaging of Pancreatic Beta-Cell
Signal-Transduction
Martin
Kohler, Daniel Nyqvist, Tilo Moede, Helene Wahlstedt,Over Cabrera, Ingo
Leibiger and Per-Olof Berggren
The development of
techniques that enable the characterization of critical parameters of
pancreatic b-cell function in a non-invasive manner is of
immense value in diabetes research. These techniques will not only allow a
better understanding of b-cell physiology and
dysfunction, but will be of practical help in the evaluation of islet material
used for transplantation into type 1 diabetic patients. In the present review
we discuss approaches, e.g. probes and microscopy/digital imaging techniques,
which are used to evaluate parameters reflecting the b-cell’s potential to convert the blood glucose
concentration signal into an appropriate secretory response of insulin. These
parameters include measurements of changes in the concentration of ATP, the
formation of NAD(P)H, changes in the mitochondrial membrane potential DYm,
changes in cytoplasmic pH, as well as changes in cytoplasmic free [Ca2+].
Moreover, we present techniques that permit online monitoring of gene
expression in living b-cells and online detection
of apoptosis of these cells. Finally, we discuss strategies that will allow the
analysis of b-cell stimulus-secretion coupling under in vivo
conditions. This includes monitoring of b-cell
function in their ‘natural setting’, i.e. the pancreas, as well as the analysis
of b-cells
within grafts following transplantation.
[Back to top] Bioluminescence Imaging of Pancreatic Islet
Transplants
Xiaojuan
Chen and Dixon B. Kaufman
Bioluminescence
imaging (BLI) modalities have been developed, refined, and used broadly in the
study of small animal models of human biology and disease. Here, we review the
importance of developing an in vivo imaging modality for real-time
monitoring islets post transplantation. In order to advance our understanding
of the pathophysiology and immunobiology of islet transplantation as they occur
in living animals, islet grafts tagged with lightemitting luciferase can be
implanted in a mouse islet transplantation model and assessed using in vivo
BLI. Some of the preliminary data, considerations of using the system, and
future applications of BLI in the field of islet transplantation research are
discussed.
[Back to top] Antibodies to Islet Beta Cell Surface Markers
Ole
D. Madsen and Klaus H. Kaestner
Insufficient functional
beta cell mass is a common denominator in most forms of diabetes. It will be
important to be able to image the functional beta cell mass during onset and/or
progression of type 1 and type 2 diabetes. It would be equally useful to
possibly image beta-cell neo-formation. With the establishment of the Beta Cell
Biology Consortium (BCBC) and its core facilities, one goal is to generate
antibody tools against stage specific surface markers characterizing the
sequential maturation from pancreatic precursors to mature beta-cells. We
believe that such antibodies will also be useful for imaging the corresponding
stages. Several BCBC research groups, as well as the Antibody and the
Functional Genomics Cores, are involved in this project. Here we outline the
overall approaches and strategies employed by the BCBC. An ultimate goal for
the Consortium is that such antibody tools will allow for the optimization of in
vitro culture conditions that will replicate normal pancreatic beta-cell
ontogeny – a prerequisite for generating clinically relevant betacell mass for
diabetes therapy.
[Back to top] Approaches for Imaging the Diabetic Pancreas:
First Results
Anna
Moore and Zdravka Medarova
Non-invasive imaging
of the diabetic pancreas is a long sought goal of clinical investigators.
Challenges remain in imaging the diabetic pancreas and studies on pancreatic
tissues are generally limited to autopsy. This review focuses on the new, fast
developing field of molecular imaging of the diabetic condition both in Type I
and Type II diabetes. The major areas under study include approaches to the
measurement of beta-cell mass (BCM), early detection of lymphocyte infiltration
in pancreatic islets during autoimmune attack and methods for visualizing
beta-cell apoptosis occurring in Type I and Type II diabetes mellitus. In spite
of being only a few years old, this new field has shown significant progress in
developing methods to study BCM, lymphocyte invasion and its consequences in
animal models. The results of these and other studies will be ultimately used
for devising therapeutic interventions, monitoring their efficacy, as well as
imaging high-risk patients. We expect that these methods will give us the
ability to detect and, possibly, follow the early progression of diabetes,
which will greatly aid and simplify the pharmacological intervention of this
disease.
[Back to top] Imaging Metabolic and Signaling Targets in
the Pancreatic Beta Cell
Louis
H. Philipson and Michael Wm. Roe
New methods are needed
to image specific molecules, cells and cellular processes to better understand
insulin secretion from islets of Langerhans in situ, the defects that
occur in diabetes mellitus, and the results of b-cell
replacement therapy. These methods are critical to further our understanding of
the biogenesis and adaptive responses of insulinsecreting cells. Imaging
techniques for these applications can be considered from those that resolve
from the nano- scale to several centimeters, with time resolutions that might
range from milliseconds to years. Static structural imaging may be helpful in
estimating b-cell mass, but this should be complemented by
functional approaches to understand the secretion defects that may be seen in
diabetes. In this brief review we discuss potential targets for functional
imaging of b-cells in vitro and in vivo.
[Back to top] In Vivo Bioluminescence Imaging to Assess Pancreatic
Islets
Alvin
C. Powers and E. Duco Jansen
Secretion of insulin
by pancreatic islets is crucial for glucose homeostasis; disorders in islet
function contribute to all types of diabetes mellitus. Transplantation of
pancreatic islets into the liver is an emerging therapy for type 1 diabetes.
However, limitations in assessing the number or mass of islets in vivo
greatly hinder efforts to understand islet physiology and pathophysiology and
to develop new therapies. Pancreatic islet size (50-200 mM), location (scattered throughout pancreas or
liver after transplantation), and mass (only 1-2% of pancreatic mass and <
1% of liver mass after transplanted into the liver) create formidable
challenges to non-invasively assess islet mass. One molecular imaging modality
being adapted to non-invasively assess islet mass is in vivo
bioluminescence imaging (BLI). BLI refers to the quantification of photons
emitted from luciferase-expressing cells after luciferin administration using a
sensitive chargecoupled device. This review summarizes approaches to use BLI to
non-invasively assess murine and human islets after transplantation into
immunodeficient mice. The ability to sequentially assess islet mass in vivo
should allow investigators to investigate the events after islet
transplantation and to develop interventions to improve islet survival.
[Back to top] Toward the Design of MR Agents for Imaging
b-Cell Function
Mark
Woods, Shanrong Zhang and A. Dean Sherry
The chemistry of Gd3+-based
MRI agents has advanced considerably during the past decade toward agents with
higher relaxivity and agents that respond to physiology and/or metabolism. This
review describes various approaches that have been taken toward the development
of responsive contrast agents and discusses the importance of fast water
exchange for advancement of targeted Gd3+-based agents with higher
sensitivity. The recent discovery of Eu3+ complexes having
extraordinarily slow water exchange has opened a new avenue in contrast agent
design based upon the chemical exchange saturation transfer (CEST) mechanism.
These new paramagnetic complexes called PARACEST agents offer new possibilities
of imaging biological functions such as tissue pH and metabolite levels. The
lower detection limits that may apply to each class of contrast agent (Gd3+-based
versus PARACEST) are discussed and the extent to which they may be applied to
the imaging of b-cells is considered.