Expression of reg/PSP, a pancreatic exocrine gene: Relationship to changes in islet β-cell mass

A cDNA termed reg was recently isolated by differential screening of a library prepared from regenerating islets isolated from pancreatic remnants of rats subjected to 90% pancreatectomy and nicotinamide treatment. This led to speculation that this gene may be involved in expansion of β-cell mass. In the current study we have measured reg expression after implantation and resection of a solid insulinoma tumor into rats, manuevers known, respectively, to reduce and reexpand the volume of β-cells in the islet. Animals with an implanted insulinoma tumor became profoundly hypoglycemic. Islet β-cells declined from the normal 75% of total islet volume to less than 30%, in concert with a marked reduction in the reg mRNA level. Removal of the tumor resulted in a sharp increase in β-cell replication, as measured by [³H]thymidine incorporation and a return to normal β-cell volume within 4 days of tumor resection. This was associated with a transient induction in reg expression compared to that in tumor-bearing animals, effectively returning the amount of reg mRNA to the levels found in normal animals within 48 h; at later time points after tumor removal (3-7 days) reg expression declined, but then rose toward normal. In situ hybridization analysis localized the initial induction in reg mRNA expression to the exocrine pancreas. Continuous infusion of insulin into normal rats for 4 days, a manuever that does not significantly reduce β-cell mass, resulted in dramatically reduced insulin mRNA in islets, but no change in the levels of reg mRNA. We conclude that the diminution in pancreatic β-cell mass caused by subcutaneous implantation of an insulinoma is associated with reduced reg gene expression and that the increase in β-cell replication after resection of the tumor is preceded by return of reg gene expression toward normal.