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Title: Investigation into glucagon like peptide-1 signalling in pancreatic β-cells
Author: Moore, Claire E. J.
ISNI:       0000 0001 3415 8496
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2008
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Glucagon like peptide-1 (GLP-1) is a GS-coupled receptor agonist that exerts multiple effects on pancreatic beta-cells, including the stimulation of insulin gene expression and secretion, growth and survival. A number of kinases are activated in response to GLP-1R activation, including extracellular regulated kinases (Erk1/2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB) and mammalian target of rapamycin mTOR, all of which contribute in regulating various aspects of beta-cell function. However, the mechanism by which GLP-1 activates these signalling pathways in pancreatic beta-cells is not fully understood. Therefore, the objectives of this thesis were to investigate how GLP-1 signals to Erk1/2. PI3K/PKB and mTOR. It has previously been reported that GLP-1 stimulated Erk1/2 activation is dependent on the influx of Ca2+ specifically through L-Type VGCC. In this thesis I provide evidence that this increase in Ca2+ activates the Ca2+ dependent phosphatase, calcineurin which in turn activates IKK leading to the activation of the MEK kinase, Tp12. Ca2+ entry through L-Type VGCC also plays a key role in stimulating insulin secretion which I show is responsible for glucose stimulated PI3K activation and PKB phosphorylation. In contrast, GLP-1 can activate PI3K independent of insulin secretion which is unable to couple to PKB. Interestingly, GLP-1 is able to potentiate glucose stimulated mTOR activation via a PI3K leading to the phosphorylation of rpS6 on Ser240/244. Moreover, GLP-1 can stimulate the phosphorylation of rpS6 on Ser235/236 which is not dependent on mTOR activation or the two currently known S6Ks, S6K1/2 or p90RSK.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available