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VOL. 73 (3), 763-784, 2007 FROM PATHOGENESIS TO THERAPEUTIC OF TYPE 2...

from the precursor pool was defective in the young GK rat. A
meaningful set of data from our group (18-20) suggests that the
permanently reduced beta-cell mass in the GK rat indeed reflects a
limitation of beta-cell neogenesis during early fetal life.

First, the comparative study of the development of GK and Wistar
pancreases indicates that the beta-cell deficit (reduced by more than
50%) starts as early as fetal age 16 days (E16) (19). The decreased
proliferation and increased apoptosis in the ductal compartment of
the pancreas where the putative endocrine precursor cells localize
suggests that the impaired development of the beta-cell in the GK
fetus could result from the failure of the proliferative and survival
capacities of the endocrine precursor cells. Importantly, recent data
from our group indicate that defective signalling through the Igf2/
Igf1-R pathway represents a primary anomaly since Igf2 and Igf1-R
protein expressions are already decreased within the GK pancreatic
rudiment at E13.5, at a time when beta-cell mass (first wave of beta
cell expansion) is in fact normal (21). Low levels of pancreatic of
Igf2 associated with beta-cell mass deficiency is maintained
thereafter within the fetal pancreas (22) (Figure 3). We also have
unpublished data related to crossbreeding protocols between non-
diabeticW and diabetic GK rats: at E18.5, Igf2 protein expression is
low in GK/GK, W/GK and GK/W pancreata, similar low values in
E18.5 crossed W/GK and GK/W fetuses, those values being close to
that observed in GK/GK fetuses of the same age. These findings
rather support the hypothesis that the pancreatic Igf2 anomaly in
the GK diabetic model is linked to a genetic determinism. This view
is also consistent with the results of genetic analyses that linked a
locus containing the gene encoding Igf2 to diabetes in the GK rat
(23). The Igf2 gene is subjected to paternal genomic imprinting (24).
However, because the Igf2 expression is similarly affected in fetuses,
regardless of whether the father is W or GK, we cannot conclude to
a simple change of Igf2 gene imprinting in the GK rat.

Second, to evaluate the capacity for beta-cell compensatory growth
during the neonatal period, we took advantage of the report that the
destruction of the beta-cell mass subsequent to streptozotocin
injection in the neonatal rat is followed by spontaneous regeneration
through both differentiation of precursor cells (neogenesis) and
increased proliferation of surviving beta-cells (18). Using such

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