Factors Regulating Islet Regeneration in the Post-Insulinoma NEDH Rat

Abstract

Increases in islet β-cell mass can be induced in a variety of experimental models, and can also occur in the face of metabolic stress, such as obesity, or in certain genetic backgrounds such as the ob/ob mouse. The factors responsible for compensatory proliferation of islet β-cells are not understood, but as this volume attests, investigation in the area is intensifying. Our own work has heretofore utilized the insulinoma-bearing New England Deaconess Hospital (NEDH) rat¹ as a model for studying islet regeneration.^2,3 Implantation of a solid insulinoma tumor into NEDH rats causes dramatic suppression of the mass and function of their islet β-cells; this suppression is reversed rapidly by surgical removal of the tumor.^2,3 We have used this model system to address two specific issues. First, we have investigated the regulation and site of expression of the reg gene, which was cloned by Okamoto and coworkers in 1988¹ by virtue of its preferential expression in a cDNA library prepared from isolated islets taken from 90% pancreatectomized, nicotinamide-injected rats, an alternate model of β-cell regeneration.^4,5 The primary sequence of reg was subsequently shown to be identical to that of the pancreatic stone protein (PSP).^6-8 an exocrine gene product whose only known function is to inhibit CaC0₃ crystal growth. thus helping to prevent chronic calcifying pancreatitis.^9-13 Second, we have begun to develop differential screening strategies designed at identifying other genes that might be involved in the expansion of β-cell mass. These initiatives are reviewed herein, and new data on the site of expression of reg/PSP is also provided.