Glucagon-like peptide-1 Induces Cell Proliferation and Pancreatic-Duodenum homeobox-1 Expression and Increases Endocrine Cell Mass in the Pancreas of Old, Glucose-Intolerant Rats

Endocrinology. 2000 Dec;141(12):4600-5. doi: 10.1210/endo.141.12.7806.

Abstract

Glucose homeostasis in mammals is maintained by insulin secretion from the beta-cells of the islets of Langerhans. Type 2 diabetes results either from primary beta-cell failure alone and/or a failure to secrete enough insulin to overcome insulin resistance. Here, we show that continuous infusion of glucagon-like peptide-1 (7-36) (GLP-1; an insulinotropic agent), to young and old animals, had effects on the beta-cell of the pancreas other than simply on the insulin secretory apparatus. Our previous studies on a rodent model of glucose intolerance, the aging Wistar rat, show that a plateau in islet size, insulin content, and beta-cell mass is reached at 13 months, despite a continuing increase in body weight. Continuous sc infusion of GLP-1 (1.5 pM/kg x min), over 5 days, resulted in normal glucose tolerance. Our current results in both young and old rats demonstrate that treatment caused an up-regulation of pancreatic-duodenum homeobox-1 (PDX-1) expression in islets and total pancreas, induced pancreatic cell proliferation, and beta-cell neogenesis. The effects on levels of PDX-1 messenger RNA were abrogated by simultaneous infusion of Exendin (9-39), a specific antagonist of GLP-1. PDX-1 protein levels increased 4-fold in whole pancreata and 6-fold in islets in response to treatment. Beta-cell mass increased to 7.2 +/- 0.58 from 4.88 +/- 0.38 mg, treated vs. control, respectively, P < 0.02. Total pancreatic insulin content also increased from 0.55 +/- 0.02 to 1.32 +/- 0.11 microg/mg total pancreatic protein. Therefore, GLP-1 would seem to be a unique therapy that can stimulate pancreatic cell proliferation and beta-cell differentiation in the pancreas of rodents.

MeSH terms

  • Aging*
  • Animals
  • Blood Glucose / analysis
  • Cell Division / drug effects*
  • Gene Expression Regulation / drug effects
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Glucose Intolerance*
  • Homeodomain Proteins / genetics
  • Insulin / blood
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Pancreas / cytology
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Peptide Fragments / pharmacology*
  • Protein Precursors / pharmacology*
  • Rats
  • Rats, Wistar
  • Trans-Activators / genetics*

Substances

  • Blood Glucose
  • Homeodomain Proteins
  • Insulin
  • Peptide Fragments
  • Protein Precursors
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Glucagon-Like Peptide 1
  • Glucagon