Overexpression of parathyroid hormone-related protein inhibits pancreatic β-cell death in vivo and in vitro

Ana Cebrian, Adolfo García-Ocaña, Karen K. Takane, Darinka Sipula, Andrew F. Stewart, Rupangi C. Vasavada

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Pancreatic β-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 β-cells using the rat insulin II promoter (RIP) display hyperinsulinemia, hypoglycemia, and islet hyperplasia, without a concomitant increase in β-cell proliferation rate or enlargement of individual β-cell size. Thus, the mechanism for increased β-cell mass is unknown. In this study, we demonstrated that β-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 β-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 β-cell death. This is also demonstrated in vitro by markedly reduced cell death rates observed in β-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 NH2-terminal PTHrP inhibits β-cell death. These findings support the concept that PTHrP overexpression increases islet mass in transgenic mice through inhibition of β-cell death.

Original languageEnglish
Pages (from-to)3003-3013
Number of pages11
JournalDiabetes
Volume51
Issue number10
DOIs
StatePublished - 1 Oct 2002
Externally publishedYes

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