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Title: Expression and roles of the lipid-responsive receptors GPR119 and GPR120 in pancreatic islets
Author: Stone, Virginia May
ISNI:       0000 0004 2730 2228
Awarding Body: Exeter and Plymouth Peninsula Medical School
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2012
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The various endocrine cell types present in mammalian Islets of Langerhans express a range of lipid-responsive G-proteln coupled receptors (GPCRs) including GPR119 and GPR120. These are each reported to be expressed In islet beta-cells and GPR 119 has been Implicated In the augmentation of glucose-stimulated insulin secretion by certain derivatives of long chain unsaturated fatty acids. By contrast GPR 120 does not appear to regulate insulin secretion and its role is unclear In addition to their ability to regulate hormone secretion long-chain fatty acids and their derivatives can also influence beta-cell viability but It IS unclear whether GPCRs are involved in mediating this response Therefore. the work undertaken in thesis has explored the possible involvement of GPR119 and GPR120 in the regulation of beta-cell viability. Long chain fatty acids exert differential effects on beta-cell viabilty according to their chain length and degree of unsaturation. Saturated molecules with chain lengths of C16 or greater are cytotoxic to beta-cells dunng chronic exposure, whereas the equivalent monounsaturates are well tolerated and can be cytoprotective Since GPR 119 and GPR 120 predominantly bind long chain unsaturated fatty acids (or their derivatives) it is possible that they might play a role. This has been studied using the clonal rat beta-cell lines BRIN-BD11 and INS-1 as well as a knockout mouse model in which GPR 120 expression was ablated. An endogenous ligand for GPR119 (oleoytetnanolamide OEA) was a potent cytoprotective agent in both clonal rat beta-cell lines However hydrolysis of OEA by endogenous fatty acid amide hydrolase (FAAH) appeared to be necessary for cytoprotection. suggesting that free oleate rather than the parent molecule. OEA. might be the protective species Since free oleate does not activate GPR 119. this implies that cytoprotection does not require GPR 119 IIgatlon In support of this. four synthetic GPR119 aqonists failed to replicate the cytoprotection seen with OEA Manipulation of GPR120 production in clonal beta-cell lines (either by shRNA mediated knock-down or by inducible over-expression) did not alter the cytoprotective capacities of unsaturated fatty acids, suggesting that GPR120 is also unlikely to be involved in the cytoprotection. However, changes in GPR 120 expression were found to lead to alterations in the levels of a number of beta-cell genes including many that regulate inflammatory responses. Consistent with this, mice fed a diet enriched in long chain fatty acids displayed enhanced macrophage Infiltration into the islets suggesting the development of a pro- Inflammatory response Further study revealed, however, that this was not Influenced by ablation of GPR 120 and that it may reflect the change in islet volume associated with high fat feeding rather than altered GPR 120 signalling per se More surprisingly, it was established in the mouse, that GPR 120 is expressed predominantly in delta-cells rather than in beta-cells and a potential role in reputation of somatostatin secretion was revealed. Overall, therefore. the studies demonstrate that GPR119 and GPR120 may play roles in the control of islet hormone secretion but they do not appear to be involved in the regulation of cell viability mediated by long chain fatty acids.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available