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

exposure to the diabetic milieu. These changes in islet function can
be ascribed, at least in part, to a loss of differentiation of beta-cells
chronically exposed to even mild chronic hyperglycaemia and
elevated plasma non-esterified fatty acids, a process referred to as
«gluco-lipotoxicity». When studied under in vitro static incubation
conditions, islets isolated from normoglycaemic (prediabetic) GK/
Par pups, amplified their secretory response to high glucose, leucine
or leucine plus glutamine to the same extent as Wistar islets (13).
Therefore, there does not exist a major intrinsic secretory defect
in the prediabetic GK/Par beta-cell, which can be considered as
normally glucose-competent at this stage. Such a view is supported
by the recent reports that chronic treatment of GK rats with phlorizin
partially improved glucose-induced insulin release (25, 26, Bailbé
and Portha, unpublished data), while hyperlipidaemia induced by
high-fat feeding markedly impaired insulin secretion (27).

Consequently, the lack of beta-cell reactivity to glucose, as seen
during the adult period when the GK/Par rats are hyperglycaemic
in the basal state, represents an acquired defect mainly related to
glucotoxicity.

Which determinants (morbid genes vs environment) for early
deficiency of the beta-cell mass in the GK/Par model?

Concerning the potential maternal influence on the development
of T2D in the GK model, Gauguier et al. (28) reported that adult
offspring of GK females crossed with Wistar males have a more
marked hyperglycaemia than adult offspring of Wistar females
crossed with GK males, suggesting higher maternal inheritance.
However, this conclusion was not confirmed in other studies and
cross-breeding experiments do not overcome the difficulty to isolate
the respective contribution of genetic vs. intrauterine environmental
factors. Recently, Gill-Randall et al. (29) developed an embryo
transfer system to examine more convincingly that major point. First,
these authors showed that offspring from GK embryos transferred
in the uterus of euglycaemic W mother still develop T2D when
adults, therefore highlighting a role for genetic factors. Second, they
showed that offspring from W embryos reared in hyperglycaemic
GK mothers were significantly hyperglycaemic at adulthood (29).

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