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.
Highlights
Recent estimates suggest a global prevalence of approximately 422 million people living with diabetes, a number expected to rise to 629 million by 2045 [1]
In this review we focus on the role of glucagon-like peptide 1 receptor (GLP-1R) trafficking as a critical component of GLP1R agonism, and how it may be possible to harness some of these processes to improve therapeutic targeting of the GLP-1R in Type 2 diabetes (T2D)
Whilst this phenomenon has not yet been studied in vivo, various reports demonstrate that the net result is that poorly internalising GLP-1RAs preserve the responsiveness of pancreatic beta cells, as measured by cumulative insulin secretion in vitro over many hours and by rechallenge experiments to reveal different rates of homologous desensitisation [55, 87], and have a beneficial net effect despite potential losses of intracellular signalling
Summary
Recent estimates suggest a global prevalence of approximately 422 million people living with diabetes, a number expected to rise to 629 million by 2045 [1]. Despite the putative role of b-arrestins as GLP-1R effectors coupled to both insulin release and protection against beta cell apoptosis [46, 47], most biased GLP-1RA studies have shown that reduced b-arrestin recruitment is associated with enhanced insulin secretion, at least under conditions of sustained stimulation This is presumed to be a consequence of b-arrestin-mediated desensitisation and/or downregulation of the GLP-1R [61]. “feeding” of GLP-1R extracellular-domainrecognising antibodies to monitor endocytosis is precluded as they compete for the orthosteric ligand binding site [99], and fluorescent agonist ligands dissociate from the receptor after entering the endocytic pathway so are informative only for the initial internalisation phase Appending biorthogonal tags such as HALO- or SNAP-tags to label the endogenous GLP-1R genomic sequence could allow a better understanding of trafficking events without the use of exogenous expression, but has not been reported to date. Adapting assays for longer stimulation times but with lower ligand concentrations would aid in understanding how GLP-1R agonist drugs influence GLP-1R trafficking over the many hours or days that they persist in the circulation
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