The role of GLP-1 in modulating the glucagon receptor in pancreatic α-cells (360G-Wellcome-202280_Z_16_Z)

Glucagon is secreted from pancreatic alpha-cells during times of hypoglycaemia. It binds to receptors on the surface of liver cells promoting gluconeogenesis, while simultaneously inhibiting glycolysis and glycogen synthesis. While this has beneficial effects during starvation, for people suffering from type 2 diabetes this significantly contributes to their overall hyperglycaemia. Little is currently known about the mechanisms by which glucagon secretion is modulated. The incretin hormone glucagon-like peptide-1 (GLP-1) inhibits glucagon secretion, but the mechanism by which it achieves this remains unclear. Expression levels of the GLP-1 receptor are extremely low in alpha-cells and GLP-1 can inhibit glucagon secretion in pancreatic cells obtained from GLP-1-/- 'knockout' mice. We therefore hypothesise that GLP-1 mediates its effects using a non-cognate receptor. GLP-1 has been documented to bind and activate the glucagon receptor (GCGR), a receptor that has been demonstrated to show coupling to various effector proteins. Thus this research project aims to characterise the precise signalling properties of the GCGR when stimulated with GLP-1 in a physiologically relevant cell line. To achieve this we will use the pancreatic alpha-cell line (alphaTC1.6) that responds to GLP-1 and secretes glucagon.