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

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

Author information

1
Department of Cell Physiology and PharmacologyUniversity of Leicester, Henry Wellcome Building, University Road, Leicester LE1 9HN, UK.
2
Department of Cell Physiology and PharmacologyUniversity of Leicester, Henry Wellcome Building, University Road, Leicester LE1 9HN, UK tph4@le.ac.uk.

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

PMID:
24994913
DOI:
10.1530/JME-13-0200
[Indexed for MEDLINE]
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