Synergistic endocrine induction by GLP-1 and TGF-beta in the developing pancreas

Pancreas. 2005 Aug;31(2):138-41. doi: 10.1097/01.mpa.0000172566.70619.58.


Objectives: Glucagon-like peptide-1 (GLP-1) is known to stimulate glucose-dependent insulin production and secretion by pancreatic beta-cells. Preliminary evidence suggests that GLP-1 may also influence endocrine differentiation from pancreatic progenitor cells. Additionally, TGF-beta signaling can also control endocrine differentiation by both inhibiting proliferation and enhancing differentiation of endocrine progenitor cells to become mature beta-cells. Here we document synergy of these two signaling pathways in the differentiation of endocrine cells in the developing pancreas.

Methods: Embryonic pancreas was harvested from mice at day 11.5 and cultured for six days with GLP-1 agonist, exendin-4, and/or TGF-beta1 ligand. Also, a pan-neutralizing TGF-beta isoform antibody was used alone or with exendin-4 to study TGF-beta inhibition in this system. Pancreatic cultures were processed for immunohistochemistry.

Results: Exogenous TGF-beta1 and exendin-4 each individually enhanced both insulin and glucagon differentiation dose-dependently. However, when combined there was an additive effect to a 4.5-fold increase in insulin-positive differentiation. We also saw suppression of amylase-positive differentiation. Surprisingly, TGF-beta pan-neutralizing antibody also gave an augmentation of endocrine differentiation by 1.5 to 2-fold, but no synergistic effect was seen with exendin-4.

Conclusion: We conclude that TGF-beta isoforms have a specific synergistic role with GLP-1 pathway signaling in early pancreatic development, toward endocrine differentiation and away from acinar differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Drug Synergism
  • Exenatide
  • Glucagon-Like Peptide 1 / agonists
  • Glucagon-Like Peptide 1 / pharmacology*
  • Islets of Langerhans* / cytology
  • Islets of Langerhans* / drug effects
  • Islets of Langerhans* / embryology
  • Mice
  • Mice, Inbred Strains
  • Pancreas, Exocrine / cytology
  • Pancreas, Exocrine / embryology
  • Peptides / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1
  • Venoms / pharmacology


  • Antibodies
  • Peptides
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide