Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1

J Mol Endocrinol. 2014 Aug;53(1):105-15. doi: 10.1530/JME-13-0200.

Abstract

Glucagon-like peptide 1 receptor (GLP1R) agonists, such as exendin-4, potentiate glucose-stimulated insulin secretion and are currently used in the management of type 2 diabetes. Interestingly, GLP1R agonists also have the ability to augment β-cell mass. In this report, we provide evidence that in the presence of glucose, exendin-4 stimulates rodent islet cell DNA replication via the activation of ribosomal protein S6 kinase 1 (S6K1) and that this is mediated by the protein kinase B (PKB)-dependent activation of mTOR complex 1 (mTORC1). We show that activation of this pathway is caused by the autocrine or paracrine activation of the IGF1 receptor (IGF1R), as siRNA-mediated knockdown of the IGF1R effectively blocked exendin-4-stimulated PKB and mTORC1 activation. In contrast, pharmacological inactivation of the epidermal growth factor receptor has no discernible effect on exendin-4-stimulated PKB or mTORC1 activation. Therefore, we conclude that GLP1R agonists stimulate β-cell proliferation via the PKB-dependent stimulation of mTORC1/S6K1 whose activation is mediated through the autocrine/paracrine activation of the IGF1R. This work provides a better understanding of the molecular basis of GLP1 agonist-induced β-cell proliferation which could potentially be exploited in the identification of novel drug targets that increase β-cell mass.

Keywords: GLP1; IGF1R; PKB/AKT; mTORC1; β-cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • DNA Replication / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Exenatide
  • Gene Knockdown Techniques
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents / pharmacology
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / metabolism*
  • Peptides / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Receptors, Glucagon / agonists
  • Ribosomal Protein S6 Kinases / metabolism*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Venoms / pharmacology*

Substances

  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Multiprotein Complexes
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Exenatide
  • TOR Serine-Threonine Kinases
  • Receptor, IGF Type 1
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Rps6kb1 protein, rat