Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/s6k1

Jianling Xie, Norhan M. El Sayed, Cheng Qi, Xuechan Zhao, Claire E. Moore, Terence P. Herbert

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22 Citations (Scopus)


Glucagon-like peptide 1 receptor (GLP1R) agonists, such as exendin-4, potentiate glucosestimulated insulin secretion and are currently used in the management of type 2 diabetes. Interestingly, GLP1R agonists also have the ability to augment b-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?-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.

Original languageEnglish
Pages (from-to)105-115
Number of pages11
JournalJournal of Molecular Endocrinology
Issue number1
Publication statusPublished or Issued - 2014
Externally publishedYes


  • GLP1
  • IGF1R
  • Mtorc1
  • Β-cell

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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