title: Exendin-4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1/S6K1.
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.
authors.affiliation: Department of Cell Physiology and PharmacologyUniversity of Leicester, Henry Wellcome Building, University Road, Leicester LE1 9HN, UK.
authors.forename: Jianling
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Cell Physiology and PharmacologyUniversity of Leicester, Henry Wellcome Building, University Road, Leicester LE1 9HN, UK.
authors.forename: Norhan M
authors.initials: NM
authors.lastname: El Sayed
authors.affiliation: Department of Cell Physiology and PharmacologyUniversity of Leicester, Henry Wellcome Building, University Road, Leicester LE1 9HN, UK.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qi
authors.affiliation: Department of Cell Physiology and PharmacologyUniversity of Leicester, Henry Wellcome Building, University Road, Leicester LE1 9HN, UK.
authors.forename: Xuechan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Cell Physiology and PharmacologyUniversity of Leicester, Henry Wellcome Building, University Road, Leicester LE1 9HN, UK.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Moore
authors.affiliation: Department of Cell Physiology and PharmacologyUniversity of Leicester, Henry Wellcome Building, University Road, Leicester LE1 9HN, UK tph4@le.ac.uk.
authors.forename: Terence P
authors.initials: TP
authors.lastname: Herbert
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077270:Exenatide; D055785:Gene Knockdown Techniques; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000819:agonists; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology*
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D046912:Multiprotein Complexes; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D017526:Receptor, IGF Type 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases
keywords: GLP1; IGF1R; PKB/AKT; mTORC1; β-cell