Impaired beta-cell regeneration after partial pancreatectomy in the adult Goto-Kakizaki rat, a spontaneous model of type II diabetes

In the Goto-Kakizaki (GK) rat, a genetic model of type II diabetes, there i s a restriction of the beta -cell mass as early as fetal age, which is main tained reduced in the adult animal. In order to investigate the beta -cell growth potential in the adult hyperglycemic GK rat, and to determine whethe r it differs from non-diabetic Wistar (W) rats, we have performed 90% pancr eatectomy (Px) in 8- to 10-week-old male animals. Spontaneous beta -cell re generation and involvement of beta -cell replication, beta -cell neodiffere ntiation from ductal precursor, and beta -cell apoptosis were evaluated by immunocytochemistry and morphometry at different time points: day 0 (DO), D 2, D7, and D14 after Px. In GK rats, deterioration of the diabetic state wi th severe and chronic hyperglycemia was evident as soon as D2, while in W/P x, normoglycemia to moderate hyperglycemia was observed. In W/Px rats, the total beta -cell mass gradually increased on D2, D7, and D14, as compared t o non-Px W rats. By contrast, in GK/Px rats, there was only a non-significa nt tendency to increased total beta -cell mass, as compared to related non- Px group. Adult GK rats displayed lower beta -cell proliferation rates comp ared to W. In response to Px, early increase of beta -cell proliferation wa s present in both W/Px and GK/Px rats on D2, but it returned to non-Px valu es in GK rats on D7 and D14, while in W/Px rats beta -cell proliferation wa s maintained increased as compared to non-Px W rats. The very low apoptotic P-cell frequency on DO, D2, D7, and D14, in both W and GK, either non-Px o r Px, did not allow us to conclude that any significant differences exist b etween the different groups. beta -cell neoformation from ducts, and more s pecifically from foci of regeneration, was found to be less activated in GK /Px rats as compared to W/Px. Together, these results suggest that in the a dult hyperglycemic GK rat undergoing Px, beta -cells still have the capacit y to regenerate, but with a lower efficiency as compared to non-diabetic W rats. This defect in the GK rat is the result of both genetic predispositio n contributing to an altered beta -cell neogenesis potential already presen t in the neonatal period, and environmental factors (chronic hyperglycemia) leading to a reduced beta -cell proliferative capacity specific to the adu lt animals.