title: Impaired beta-cell regeneration after partial pancreatectomy in the adult Goto-Kakizaki rat, a spontaneous model of type II diabetes.
abstract: In the Goto-Kakizaki (GK) rat, a genetic model of type II diabetes, there is a restriction of the beta-cell mass as early as fetal age, which is maintained reduced in the adult animal. In order to investigate the beta-cell growth potential in the adult hyperglycemic GK rat, and to determine whether it differs from non-diabetic Wistar (W) rats, we have performed 90% pancreatectomy (Px) in 8- to 10-week-old male animals. Spontaneous beta-cell regeneration and involvement of beta-cell replication, beta-cell neodifferentiation from ductal precursor, and beta-cell apoptosis were evaluated by immunocytochemistry and morphometry at different time points: day 0 (D0), D2, D7, and D14 after Px. In GK rats, deterioration of the diabetic state with severe and chronic hyperglycemia was evident as soon as D2, while in W/Px, normoglycemia to moderate hyperglycemia was observed. In W/Px rats, the total beta-cell mass gradually increased on D2, D7, and D14, as compared to non-Px W rats. By contrast, in GK/Px rats, there was only a non-significant tendency to increased total beta-cell mass, as compared to related non-Px group. Adult GK rats displayed lower beta-cell proliferation rates compared to W. In response to Px, early increase of beta-cell proliferation was present in both W/Px and GK/Px rats on D2, but it returned to non-Px values in GK rats on D7 and D14, while in W/Px rats beta-cell proliferation was maintained increased as compared to non-Px W rats. The very low apoptotic beta-cell frequency on D0, D2, D7, and D14, in both W and GK, either non-Px or Px, did not allow us to conclude that any significant differences exist between the different groups. beta-cell neoformation from ducts, and more specifically 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 adult hyperglycemic GK rat undergoing Px, beta-cells still have the capacity 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 predisposition contributing to an altered beta-cell neogenesis potential already present in the neonatal period, and environmental factors (chronic hyperglycemia) leading to a reduced beta-cell proliferative capacity specific to the adult animals.
authors.affiliation: Laboratory of Physiopathology of Nutrition, CNRS ESA 7059, Université Paris 7/Denis Diderot, 2 place Jussieu, 75251 Paris Cedex 05, France. plachot@paris7.jussieu.fr
authors.forename: C
authors.initials: C
authors.lastname: Plachot
authors.forename: J
authors.initials: J
authors.lastname: Movassat
authors.forename: B
authors.initials: B
authors.lastname: Portha
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000032:analysis; D002454:Cell Differentiation; D002455:Cell Division; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology* / Q000601:surgery; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000473:pathology / Q000601:surgery; D006946:Hyperinsulinism / Q000473:pathology / Q000601:surgery; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D010179:Pancreas / Q000166:cytology / Q000502:physiology* / Q000601:surgery; D010180:Pancreatectomy; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology
chemical_list: D001973:Bromodeoxyuridine