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Ontogeny of Regeneration of ß-Cells in the Neonatal Rat after Treatment with Streptozotocin

Lawson Health Research Institute, St. Joseph’s Health Care (S.T., E.A., D.J.H.), and Departments of Medicine (E.A., D.J.H.), Physiology and Pharmacology (D.J.H.), and Pediatrics (D.J.H.), University of Western Ontario, London, Ontario, Canada N6A 4V2

Address all correspondence and requests for reprints to: Dr. David J Hill, Lawson Health Research Institute, St. Joseph’s Health Care, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2. E-mail: dhill{at}lri.sjhc.london.on.ca.

We induced partial ß-cell loss within the pancreas of neonatal rats using streptozotocin (STZ) to better characterize the mechanisms leading to ß-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 ß-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 -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 ß-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 ß-cells, and this is associated with hyperplasia of -cells with an altered phenotype of increased GLP-1 synthesis. The target cells of GLP-1 probably include immature ß-cells that coexpress proglucagon.

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