Biology Reference
In-Depth Information
abnormalities and increased insulin sensitivity, with the duration of
the treatment positively correlating with insulin sensitivity in these
patients (
188-190
).
To date Epo expression by pancreatic cells has not been
observed. However EpoR was expressed on islets of both human
and non-human primates following Epo supplementation, or after
transduction with an Adenoviral vector expressing high levels of
Epo, affording protection of the islets from cytokine-induced
destruction (
49, 191
). In addition, performance assessment of
transduced islets transplanted into diabetic immunodeficient mice
showed that overexpression of Epo conferred a functional advan-
tage (
191
) and is also associated with a decrease in body weight
(
192
). A number of in vitro and in vivo papers have now provided
evidence that Epo is beneficial for b cell survival. In NIT-1 pancre-
atic cells, the PI3K inhibitor LY294002 abrogated the anti-apop-
totic activity of Epo, indicating that activation of Akt was required
for Epo-induced inhibition of cytokine-induced apoptosis (see
Fig.
1
) (
193
). In another study upregulation of Bcl-2, and con-
comitant downregulation of Bax and caspase 3, has also been sug-
gested as a mechanism through which Epo can protect neonatal
islet cells. In vivo diabetic rodent models also advocate direct
effects of Epo on pancreatic b cells (see Fig.
2
, pathway 6) promot-
ing anti-apoptosis, proliferation, and angiogenesis signaling
through its cognate receptor and downstream effector, JAK2, thus
increasing b-cell mass (
194
). A very recent study administering a
single dose of the novel Epo receptor agonist CNTO 530 to diet-
induced obese mice resulted in improved glucose tolerance and
insulin sensitivity at least in part from increased uptake of glucose
by skeletal and cardiac muscle (
195
). The molecular mechanism(s)
responsible for translating Epo receptor signaling into improved
glucose tolerance are yet to be revealed and much more data is
required to better understand its beneficial mechanism of action in
general. However it is clear that Epo-induced pathways involving
JAK2, Akt phosphorylation, and altered expression of several
downstream apoptosis-related proteins, such as Bcl-2 and Bax as
seen in other tissues, are likely to be a recurrent theme.
8
The Endothelium
Epo was shown to act on endothelial cells in vivo and in vitro
having growth and chemotactic effects (
40
). In fact it has been
suggested that many of the observed non-erythroid cytoprotec-
tive effects of Epo are mediated by second messengers released
from endothelial cells (see Fig.
2
) (
196
). The observation that
development of the conditional non-hematopoietic EpoR knock-
out mouse is normal further supports this view. Equally impor-
tant, Epo has been shown to facilitate vascular repair and thereby
Search WWH ::
Custom Search