A Glimmer of Hope for Diabetes

Po Man Suen, Po Sing Leung
Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong.
Shatin, New Territories, Hong Kong
Diabetes mellitus (DM) is a devastating
disease afflicting over 200 million people in
the world. While type 1 diabetes mellitus
(T1DM) is characterized by autoimmune
destruction of islets, it is now well-recognized
that reduced pancreatic beta cell mass and
insulin secretory failure play a pivotal role in
the development and progression of type 2
diabetes mellitus (T2DM). Routine exogenous
insulin treatment seems to have been
dominant over the past decades,
notwithstanding episodes of inadequate
control of chronic hyperglycemia leading to
microvascular complications or increased
incidences of hypoglycemia [1]. Recent
success in islet transplantation protocol has
been proven to restore the physiological
secretion of insulin in patients with T1DM
and in some patients with severe forms of
T2DM. However, beta-cell replacement
therapy is significantly hampered by an
acutely limited source of transplantable
human islets from cadaveric donors [2]. Of
great interest in this context is the possible
exploitation of cellular medicine for providing
alternative sources of functional islet cells [3].
Notably, the possibility of using stem cells
and pluripotent or multipotent cells which can
self-renew and differentiate into multiple cell
lineages, either embryo-derived or fetal/adult
tissue-derived, in treating diabetic patients is
now gaining credibility [4].
Insulin-secreting cells have been shown to
develop from stem/progenitor cells isolated
from a variety of tissues, such as recently
reported in bone marrow, liver and intestinal
epithelium. However, no clearly identifiable
pancreatic stem cells (PSCs) have been found
until now, despite considerable evidence that
such cells are present in the islet or ductal
cells of the pancreas [5]. While the
mechanism for beta-cell mass expansion
either from existing beta-cell expansion [6] or
from stem cell activation, is still under debate,
a conceptual mechanism regarding beta-cell
differentiation occurs; to this end, epithelial to
mesenchymal transition (EMT) was suggested
to take place in the pancreas. It thus proposes
the dedifferentiation of fully differentiated
epithelial cells into stem cells of a
“mesenchymal” phenotype which, in turn,
redifferentiate back into epithelial cells in a
new location [7]. An established
neuroepithelial protein nestin, which was
reported as a marker for endocrine progenitor
cells in the early 2000s, is controversial.
These nestin-positive putative PSCs when
exposed to different growth factors or
microenvironments give rise to islet-like cell
clusters (ICCs) which temporarily express
multiple endocrine hormones [8]. In addition
to the minimal response from such PSCs to
glucose challenge, it has been shown that
those PSC-derived-beta-cells acquired only an
immature beta-cell phenotype. Taken together,
these results represent the inability of the
existing cocktail of growth factors such as
nicotinamide, betacellulin, glucagon-like
peptide, or activin A to induce full
differentiation of PSCs into functional

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JOP. J Pancreas (Online) 2005; 6(5):422-424.
JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 6, No. 5 –September 2005. [ISSN 1590-8577]
insulin-secreting cells. To this end, the
exploration of novel growth factors is of
paramount importance [9].
In this respect, our preliminary data have
demonstrated that PSCs with stem cell
markers, such as nestin, ATP-binding cassette
transporter (ABCG2) and c-kit, can be
isolated and cultured from human fetal
pancreases. Such PSCs, which can be
extensively expanded and passaged, also
possess the receptors of certain growth factors
including hepatocyte growth factor (c-met),
glucagon-like peptide (GLP-1R) and
epidermal growth factor (erbB1). Intriguingly,
a novel factor called PDZ-domain containing
2 (PDZD2) for growth and insulin gene
expression was richly localized in the nucleus
and perinuclear membrane of these PSCs [10].
This protein is of highly homologous with
interleukin 16 (IL-16) which has the function
of growth and differentiation in various
tissues [11]. While their functional similarities
remain unknown, our recent findings suggest
that a 37 kDa peptide secreted from PDZD2
may exert a mitogenic effect on the PSCs
(unpublished data).
PSCs are definitely a potential approach to
islet cell replacement therapy; however, much
more work is essential for full maturation of
the in vitro growth of insulin-secreting cells.
The identification of 1) a specific marker for
the lineage-tracing studies, 2) temporal gene
expressions during the developmental stages
of PSC-derived islets, and 3) appropriate
cocktails of
growth factors or
microenvironments essential for beta-cell
differentiation will represent a major
breakthrough for the therapeutic intervention
for T1DM in the near future.
Diabetes Mellitus; Insulin;
Intermediate Filament Proteins; Nerve Tissue
Proteins; Pancreas; Stem Cells
Abbreviations ABCG2: ATP-binding cassette
transporter; DM: diabetes mellitus; EMT:
epithelial to mesenchymal transition; GLP:
glucagon-like peptide; ICCs: islet-like cell
clusters; IL-16: interlukin 16; PDZD2:
PDZ-domain containing 2; PSCs: pancreatic
stem cells; T1DM: type 1 diabetes mellitus;
T2DM: type 2 diabetes mellitus
Acknowledgements The work described in
this paper was supported by the Competitive
Earmarked Research Grant from the Research
Grants Council of Hong Kong (Project No.
CUHK4364/04M), awarded to PSL
Po Sing Leung
Department of Physiology
Faculty of Medicine
The Chinese University of Hong Kong
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