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

Taken together, these data are consistent with the notion that a
poor proliferation and/or survival of the endocrine precursors during
foetal, neonatal and adult life will result in poor development of the
beta-cell mass, as well as a decreased pool of endocrine precursors
in the pancreas, and hence to an impaired capacity of regeneration
by neogenesis (either primary in the fetus or compensatory in the
newborn and the adult). Finally, the earliest alteration detected in
the GK/Par rat targets the size of the beta-cell population. It is
conceivable that some genes among those involved in the GK/Par
diabetes belong to the subset of genes controlling early beta-cell
development.

Functionally defective beta-cells

In adult GK/Par rats, the plasma insulin release in vivo in
response to intravenous glucose was lacking (12-14). In vitro studies
of insulin release with the isolated perfused pancreas or with
perifused islets indicated that both the early and late phases of
glucose-induced insulin release were markedly affected in the adult
GK/Par rat. We have shown that impaired glucose-induced insulin
release in GK/Par islets was associated with perturbation of multiple
intracellular sites. Since this aspect has been recently and extensively
reviewed by us and others (13, 14), it will not be further considered
in this paper. Figure 4 illustrates a compendium of the abnormal
intracellular sites so far identified in the diabetic GK beta-cell.

WHAT ARE THE MECHANISMS THAT UNDERLIE THE
PROGRAMMING OF THE GK BETA-CELL DYSFUNCTIONS?

Is beta-cell functional failure due to the abnormal metabolic
environment (gluco-lipotoxicity)?

In the GK/Par rat, basal hyperglycaemia and normal to very mild
hypertriglyceridaemia are observed only after weaning (13, 15). The
onset of a profound alteration in glucose-stimulated insulin secretion
by the GK beta-cell (after weaning) is time-correlated with the

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