The Interplay of Glucagon-Like Peptide-1 Receptor Trafficking and Signalling in Pancreatic Beta Cells

Abstract

The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) which mediates the effects of GLP-1, an incretin hormone secreted primarily from L-cells in the intestine and within the central nervous system. The GLP-1R, upon activation, exerts several metabolic effects including the release of insulin and suppression of appetite, and has, accordingly, become an important target for the treatment for type 2 diabetes (T2D). Recently, there has been heightened interest in how the activated GLP-1R is trafficked between different endomembrane compartments, controlling the spatial origin and duration of intracellular signals. The discovery of "biased" GLP-1R agonists that show altered trafficking profiles and selective engagement with different intracellular effectors has added to the tools available to study the mechanisms and physiological importance of these processes. In this review we survey early and recent work that has shed light on the interplay between GLP-1R signalling and trafficking, and how it might be therapeutically tractable for T2D and related diseases.

Keywords: GLP-1; GLP-1R; biased agonism; pancreatic beta cells; receptor trafficking.

Figure 1

A summary of the effects of GLP-1 on insulin synthesis, secretion, beta cell proliferation, neogenesis and apoptosis inhibition. In pancreatic beta cells, GLP-1R signalling is predominantly via Gα_s which mediates increases in cAMP to activate Epac and PKA. These have a range of effects, as described in the main text and depicted in this figure. These and other pathways promote increases in insulin gene transcription, synthesis and secretion. Figure created using BioRender.com.

Figure 2

A summary of GLP-1R trafficking. GLP-1 receptors are internalised through clathrin-dependent and/or clathrin-independent mechanisms and subsequently transported to sorting endosomes/early endosomes. From here they can either be recycled back to the plasma membrane via a fast recycling pathway (short cycle), a slow recycling (long cycle), or be targeted for degradation to lysosomes via multi vesicular bodies/late endosomes. Figure created using BioRender.com.