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

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.