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Diabetes 51:3003-3013, 2002
© 2002 by the American Diabetes Association, Inc.

Overexpression of Parathyroid Hormone-Related Protein Inhibits Pancreatic ß-Cell Death In Vivo and In Vitro

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

From the Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

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


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