Ontogeny of Regeneration of Beta-Cells in the Neonatal Rat After Treatment With Streptozotocin

Endocrinology. 2006 May;147(5):2346-56. doi: 10.1210/en.2005-0396. Epub 2006 Feb 16.

Abstract

We induced partial beta-cell loss within the pancreas of neonatal rats using streptozotocin (STZ) to better characterize the mechanisms leading to beta-cell regeneration postnatally. Rats were administered either STZ (70 mg/kg) or buffer alone on postnatal d 4, and the endocrine pancreas was examined between 4 and 40 d later. STZ-treated rats showed an approximately 60% loss of existing beta-cells and a moderate hyperglycemia (<15 mm glucose), with levels returning to near-control values after 20 d. Within preexisting islets, there was increased cell proliferation in both insulin- and glucagon-positive cells at 8 d as well as alpha-cell hyperplasia. These were associated with increased pancreatic content and circulating levels of glucagon. Pancreatic levels of glucagon-like polypeptide-1 (GLP-1) were increased 8 d after STZ compared with control values, and the GLP-1/glucagon ratio changed in favor of GLP-1. Administration of a GLP-1 receptor antagonist, GLP-1-(9-39), resulted in decreased recovery of beta-cells after STZ and worse glucose tolerance. Atypical glucagon-positive cells were found within islets that colocalized pancreatic duodenal homeobox-1 or glucose transporter-2. Pancreatic levels of insulin mRNA did not return to control values until 40 d after STZ. Insulin-positive cells were found after 8 d that colocalized glucagon and GLP-1. The model shows that the pancreas of the young rat can rapidly regenerate a loss of beta-cells, and this is associated with hyperplasia of alpha-cells with an altered phenotype of increased GLP-1 synthesis. The target cells of GLP-1 probably include immature beta-cells that coexpress proglucagon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Proliferation
  • DNA Primers / chemistry
  • Female
  • Glucagon / chemistry
  • Glucagon / metabolism
  • Glucose / metabolism
  • Immunohistochemistry
  • Insulin / metabolism
  • Insulin-Secreting Cells / physiology*
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Microscopy, Fluorescence
  • Pancreas / metabolism
  • Proglucagon / metabolism
  • RNA, Messenger / metabolism
  • Radioimmunoassay
  • Rats
  • Rats, Wistar
  • Regeneration*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Streptozocin / pharmacology*
  • Time Factors

Substances

  • DNA Primers
  • Insulin
  • RNA, Messenger
  • Proglucagon
  • Streptozocin
  • Glucagon
  • Glucose