Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.555480
Title: Hormonal and nutrient signalling to protein kinase B and mammalian target of rapamycin in pancreatic beta-cells
Author: Mostafa, Norhan Mohamed El-Sayed B.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2012
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Abstract:
Objectives: Protein kinase B (PKB) and mammalian target of rapamycin (mTOR) signalling pathways control several critical cellular processes including metabolism, protein synthesis, proliferation and cell survival. Glucagon-like peptide-1(GLP-1) stimulates β-cell proliferation and protects cells against cytokine induced apoptosis via activation of mTORC1 and PKB. Amino acids are also able to regulate mTOR though the role of amino acid transporters in the regulation of amino acid-dependent regulation of mTORC1 is unknown. The regulations of PKB and mTORC1 by GLP-1 and amino acids have been the subjects of intense study; despite this, many questions remain to be answered. Therefore, this study aims to investigate the transduction pathways by which GLP-1 and amino acids regulate PKB/ mTORC1 activation. Results: I showed that GLP-1 in the presence of glucose induced activation of mTORC1 in rat islets of Langerhans and β-cell lines and this was sensitive to PKB inhibitor, AKTi. GLP-1 also potentiated glucose-stimulated mTORC1 activation via a calcium and PI3K dependent mechanism. Diazoxide, an inhibitor of exocytosis, significantly reduced GLP1-induced PKB and mTORC1 activation. siRNA mediated knock-down of insulin receptor expression was unable to inhibit GLP1-stimulated PKB or mTORC1 activation. In contrast, siRNA mediated knockdown of the IGF-1 receptor effectively blocked GLP1-stimulated PKB and mTORC1 activation. Incubation of rat islets in medium without Glutamine or System L amino acids blocked mTORC1 activation in response to insulin. Inhibition of SNAT2 with methylaminoisobutyrate or silencing of SNAT2 expression with small interfering RNAs inhibited mTOR activation. Inhibition of LAT1 by 2-aminobicyclo(2,2,1) hepatane carboxylic acid (BCH) blocked PKB and mTORC1 activation. Conclusion: In pancreatic β-cells, acute activation of PKB and mTORC1 by GLP1 is mediated via the activation of the IGF1 receptor, presumably through the autocrine effect of IGF. The plasma membrane amino acid exchangers (SNAT2 and LAT1) can regulate mTORC1 activity suggesting that they can play a key role in control β-cell function.
Supervisor: Herbert, Terence. ; Willars, Gary. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.555480  DOI: Not available
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