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Endocrinology Vol. 139, No. 9 3743-3751
Copyright © 1998 by The Endocrine Society

ARTICLES

Progressive Pancreatic Islet Hyperplasia in the Islet-Targeted, Parathyroid Hormone-Related Protein-Overexpressing Mouse1

Scott E. Porter, Robert L. Sorenson, Pamela Dann, Adolfo Garcia-Ocana, Andrew F. Stewart and Rupangi C. Vasavada

Yale University School of Medicine (S.E.P., P.D., R.C.V.), New Haven, Connecticut 06520; The Department of Cell Biology (R.L.S.), The University of Minnesota, Minneapolis, Minnesota 55455; The Division of Endocrinology (A.G.-O., A.F.S.), The University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213; and the Department of Veterans Affairs, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Andrew F. Stewart M.D., Division of Endocrinology, E-1140 BST, University of Pittsburgh Medical Center, 3550 Terrace Street, Pittsburgh, Pennsylvania 15213. E-mail: stewart{at}med1.dept-med.pitt.edu

PTH-related protein (PTHrP) is a paracrine/autocrine factor produced in most cell types in the body. Its functions include the regulation of cell cycle, of differentiation, of apoptosis, and of developmental events. One of the cells which produces PTHrP is the pancreatic ß cell. We have previously described a transgenic mouse model of targeted overexpression of PTHrP in the ß cell, the RIP-PTHrP mouse. These studies showed that PTHrP overexpression markedly increased islet mass and insulin secretion and resulted in hypoglycemia. Those studies were limited to RIP-PTHrP mice of 8–12 weeks of age.

In the current report, we demonstrate that PTHrP overexpression induces a progressive increase in islet mass over the life of the RIP-PTHrP mouse, and that, in contrast to some other models of targeted PTHrP overexpression, the phenotype is not developmental, but occurs postnatally. The marked increase in islet mass is not associated with a measurable increase in ß cell replication rates. A further slowing in the normally low islet apoptosis rate could not be demonstrated in the RIP-PTHrP islet. Thus, the marked increase in islet mass in the RIP-PTHrP mouse is unexplained in mechanistic terms. Finally, RIP-PTHrP mice are resistant to the diabetogenic effects of streptozotocin.

The mechanisms responsible for the increase in islet mass in the RIP-PTHrP mouse likely lie in either very subtle changes in islet turnover or in early steps in islet differentiation and development. The ability of PTHrP to increase islet mass and function, as well as its ability to attenuate the diabetogenic effects of streptozotocin, indicate that further study of PTHrP on islet development and function are important and may lead to therapeutic strategies in diabetes mellitus.




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