Abstract
Diabetes and its many associated complications are an increasingly heavy burden on global healthcare systems. This has made the identification of new therapeutic targets an important strategy for countering the pandemic. Overall diabetes is characterised by hyperglycaemia, with Type 2 being the most common form, accounting for ~90 % of all diabetes patients. This is further characterised by dysfunction of insulin secretion and/or action. Insulin, an anabolic hormone secreted by beta cells of the islets of Langerhans in the pancreas, is the main mechanism to facilitate the uptake and storage of glucose from the blood. Therefore, issues in this pathway can directly affect blood glucose levels.G-protein Coupled Receptors (GPCRs) are among the most targeted receptors by approved drugs, with over 30 % of approved drugs targeting GPCRs. However, there are numerous GPCRs whose function have not yet been fully elucidated, particularly of interest are orphan GPCRs whose endogenous ligands are unknown. One such orphan receptor, GPR75, has been linked to obesity, diabetes and insulin secretion. RANTES (CCL5) has been postulated as a GPR75 ligand and to stimulate and potentiate glucose-stimulated insulin secretion (GSIS) from beta cells. Therefore, we aimed to elucidate the role of GPR75 in insulin secretion and explore GPR75’s function in pancreatic beta cells.
To investigate the role of GPR75 in beta cell function we isolated islets from GPR75 CRISPR knockout (GPR75KO) mice. GPR75KO showed significantly reduced GSIS compared to wild type (WT), suggesting that GPR75 is a tonic regulator of beta cell function. Next, we undertook pancreatic histology to assess pancreatic structure and beta cell composition. Following a 12-week high-fat diet, we observed no significant difference in beta cell number or in surface area of individual beta cells between female GPR75KO and WT. However, the overall surface area of these GPR75KO pancreases were significantly smaller than WT suggesting reduced acinar cell mass. Finally, we tested the putative GPR75 ligand, RANTES, however this had little effect on GSIS in the INS1E cell line and murine islets regardless of the presence of GPR75.
Overall, we showed that GPR75KO resulted in a stunted GSIS response following a regular chow diet, that RANTES had no effect on GSIS and that GPR75KO reduced pancreatic surface area following high fat diet. Together with data on GPR75 expression in beta cells, these data highlights GPR75 as a receptor of interest to the field of metabolic syndrome and diabetes.
| Date of Award | 2024 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | James Cantley (Supervisor), Fiona Murray (Supervisor) & Colin Murdoch (Supervisor) |