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BERNARD PORTHA AN. R. ACAD. NAC. FARM.

the beta-cell population cannot be ascribed to increased beta-cell
apoptosis but is related, at least partly, to significantly decreased beta-
cell replication (13). Moreover, the adult GK/Par pancreas exhibits two
different populations of islets: large islets which are disrupted by
connective tissue (15) and display heterogeneity in the staining of the
beta-cells, and small islets with heavily stained beta-cells and normal
architecture.

The islets of adult GK/Par rats show decreased beta-cell number
and low insulin content compared with control islets. The islet DNA
content was decreased to a similar extent, consistent with our
morphometric data, which indicates that there is no major change in
the relative contribution of beta-cells to total endocrine cells in the
GK islets. In addition, the insulin content, when expressed relative
to DNA, remains lower in GK islets than in control (inbred Wistar/
Par) islets, which supports some degranulation in the beta-cells of
diabetic animals (16).

Moreover, using a complementary approach that associated
gene expression analysis (Affymetrix microarrays), quantitative
RT-PCR and immunohistochemical studies of pancreata as a
function of hyperglycaemia duration, we have recently demonstrated
that an inflammatory reaction is associated with islet fibrosis
in 4-month-old diabetic GK rats according to a process reminiscent
of microangiopathy (17). These alterations worsened with
hyperglycaemia duration and might contribute to enhanced GK beta-
cell impairment.

Decreased beta-cell population due to early limitation of
beta-cell neogenesis

Extensive follow-up of the animals after delivery revealed that
GK/Par pups become overtly hyperglycaemic for the first time after
three to four weeks of age only. Nevertheless, total beta-cell mass in
GK neonates is clearly decreased (by 60%) when compared with
Wistar rats (Figure 2) (15). We first previously demonstrated that the
early beta-cell growth retardation in the GK/Par model cannot be
ascribed to decreased beta-cell replication, nor to increased apoptosis
(15). We therefore postulated that the recruitment of new beta-cells

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