Overexpression of parathyroid hormone-related protein inhibits pancreatic beta-cell death in vivo and in vitro.
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.
D000367:Age Factors; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D015870:Gene Expression / Q000502:physiology; D051273:Glucose Transporter Type 2; D007113:Immunity, Innate; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013311:Streptozocin / Q000633:toxicity; D051020:bcl-X Protein
D000903:Antibiotics, Antineoplastic; C494812:Bcl2l1 protein, mouse; D051273:Glucose Transporter Type 2; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D044162:Parathyroid Hormone-Related Protein; D036361:Peptide Hormones; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; D013311:Streptozocin