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

Thus, in W rats with no genetic risk of diabetes, exposure to
hyperglycaemia in utero (as seen in the GK pregnant mother)
increases the risk of hyperglycaemia in adult life (29), this clearly
illustrating a diabetogenic role for the GK intrauterine environment.

Concerning the impact of maternal hyperglycaemia (as induced
experimentally in the rat by streptozotocin (30) or glucose infusion
(31) on beta-cell function specifically, it has been long recognized that
it persists into adult life and the second and third generation
offsprings. Another recent illustration is offered by observations in rat
pups reared artificially on a high carbohydrate (HC) milk formula
(32): such alteration of nutrition during the suckling period only,
induces persistent adaptation of energy metabolism in adulthood
(obesity, glucose intolerance, impaired insulin secretion) and the HC
fed females spontaneously transmitted their metabolic characteristics
to their progeny without the pups themselves having to undergo any
nutritional treatment (32). Taken as a whole, information from the HC
rat pup model (32) and from the offspring of mildly hyperglycaemic
rat mothers (33) suggests that hyperglycaemia experienced during the
foetal and/or early postnatal life contributes to programming of
the endocrine pancreas. Such a scenario also potentially applies to the
GK/Par model, as GK/Par mothers are slightly hyperglycaemic
through their gestation and during the suckling period. Therefore, the
gestational diabetic pattern of the GK/Par mothers may contribute per
se (besides inherited disease genes) to establish and/or maintain the
transmission of endocrine pancreas programming from one GK/Par
generation to the next one. By such mechanism, the GK/Par rat can
be viewed as a model of developmental programming for T2D
(associated to programming for low beta-cell mass), with a stable
transgenerational transmission.

Two functional point mutations in the promoter region of the
adenyl cyclase type 3 (AC3) gene have been reported in both islets
and peripheral blood of GK rats in the Stockholm colony and are
associated to GK beta-cell AC3 over expression and increased cAMP
generation (34). The contribution if any, of such a mutation to the
GK beta-cell growth defect is so far unknown.

Gauguier et al. (23) using a quantitative trait locus (QTL)
approach, have identified six independently segregating loci

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