Ontogeny of regeneration of beta-cells in the neonatal rat after treatment with streptozotocin.
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.
Lawson Health Research Institute, St. Joseph's Health Care, London, Ontario, Canada.
Sandra
S
Thyssen
Edith
E
Arany
D J
DJ
Hill
D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005934:Glucagon / Q000737:chemistry / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D010179:Pancreas / Q000378:metabolism; D052336:Proglucagon / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013311:Streptozocin / Q000494:pharmacology*; D013997:Time Factors
D017931:DNA Primers; D007328:Insulin; D012333:RNA, Messenger; D052336:Proglucagon; D013311:Streptozocin; D005934:Glucagon; D005947:Glucose