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

Xie, J., El Sayed, N. M., Qi, C. , Zhao, X., Moore, C. E. and Herbert, T. P. (2014) Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/s6k1. Journal of Molecular Endocrinology, 53 (1). pp. 105-115. ISSN 0952-5041

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Item Type:Article
Item Status:Live Archive

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:Diabetes
Divisions:College of Science > School of Pharmacy
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ID Code:28217
Deposited On:07 Nov 2017 14:51

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