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Diabetes 53:3120-3130, 2004
© 2004 by the American Diabetes Association, Inc.

Characterization of Mice Doubly Transgenic for Parathyroid Hormone-Related Protein and Murine Placental Lactogen

A Novel Role for Placental Lactogen in Pancreatic ß-Cell Survival

Yuichi Fujinaka, Darinka Sipula, Adolfo Garcia-Ocaña, and Rupangi C. Vasavada

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

Transgenic overexpression of either parathyroid hormone-related peptide (PTHrP) or mouse placental lactogen type 1 (mPL1) in pancreatic ß-cells, using the rat insulin II promoter (RIP), results in islet hyperplasia either through prolonged ß-cell survival or through increased ß-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 ß-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 ß-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 ß-cells, placing it among the few proteins that can improve function and proliferation and prolong the survival of ß-cells. Placental lactogen 1 is an attractive target for future therapeutic strategies in diabetes.

Address correspondence and reprint requests to Rupangi C. Vasavada, Ph.D., Division of Endocrinology, BST E-1140, University of Pittsburgh School of Medicine, 3550 Terrace St., Pittsburgh, PA 15213. E-mail: vasavada{at}msx.dept-med.pitt.edu


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