Characterization of mice doubly transgenic for parathyroid hormone-related protein and murine placental lactogen: a novel role for placental lactogen in pancreatic beta-cell survival.
Transgenic overexpression of either parathyroid hormone-related peptide (PTHrP) or mouse placental lactogen type 1 (mPL1) in pancreatic beta-cells, using the rat insulin II promoter (RIP), results in islet hyperplasia either through prolonged beta-cell survival or through increased beta-cell proliferation and hypertrophy, respectively. For determining whether the two proteins might exert complementary, additive, or synergistic effects on islet mass and function when simultaneously overexpressed in beta-cells in vivo, RIP-PTHrP and RIP-mPL1 mice were crossed to generate mice doubly transgenic for PTHrP and mPL1. These double-transgenic mice displayed marked islet hyperplasia (threefold), hypoglycemia, increased beta-cell proliferation (threefold), and resistance to the diabetogenic and cytotoxic effects of streptozotocin compared with their normal siblings. Although the phenotype of the double-transgenic mice was neither additive nor synergistic relative to their single-transgenic counterparts, it was indeed complementary, yielding the maximal salutary phenotypic features of both individual transgenes. Finally, mPL1, for the first time, was shown to exert a protective effect on the survival of beta-cells, placing it among the few proteins that can improve function and proliferation and prolong the survival of beta-cells. Placental lactogen 1 is an attractive target for future therapeutic strategies in diabetes.
Fujinaka
Yuichi
Y
Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Sipula
Darinka
D
Garcia-Ocaña
Adolfo
A
Vasavada
Rupangi C
RC
D000818:Animals; D001483:Base Sequence; D002470:Cell Survival; D017931:DNA Primers; D005786:Gene Expression Regulation; D006965:Hyperplasia; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000166:cytology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D010928:Placental Lactogen / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats
D017931:DNA Primers; D007328:Insulin; D044162:Parathyroid Hormone-Related Protein; D010928:Placental Lactogen