Overexpression of parathyroid hormone-related protein inhibits pancreatic beta-cell death in vivo and in vitro.
Diabetes
; 51(10): 3003-13, 2002 Oct.
Article
em En
| MEDLINE
| ID: mdl-12351440
ABSTRACT
Pancreatic beta-cell survival is critical in the setting of diabetes as well as in islet transplantation. Transgenic mice overexpressing parathyroid hormone-related protein (PTHrP) targeted to beta-cells using the rat insulin II promoter (RIP) display hyperinsulinemia, hypoglycemia, and islet hyperplasia, without a concomitant increase in beta-cell proliferation rate or enlargement of individual beta-cell size. Thus, the mechanism for increased beta-cell mass is unknown. In this study, we demonstrated that beta-cells of transgenic mice are resistant to the cytotoxic effects of streptozotocin (STZ) in vivo, as documented by a sixfold reduction in the rate of STZ-induced beta-cell death in RIP-PTHrP mice relative to their normal siblings. The reduced cell death in transgenic mice is due neither to their increased islet mass nor to a decrease in their sensing of STZ, but rather results from PTHrP-induced resistance to beta-cell death. This is also demonstrated in vitro by markedly reduced cell death rates observed in beta-cells of transgenic mice compared with normal mice when cultured in the absence of serum and glucose or in the presence of STZ. Finally, we demonstrated that NH(2)-terminal PTHrP inhibits beta-cell death. These findings support the concept that PTHrP overexpression increases islet mass in transgenic mice through inhibition of beta-cell death.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Limite:
Animals
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article