Downregulation and Desensitisation: How Incretin Receptor Internalisation Varies Across Agonist Classes

 

The incretin receptors—the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR)—are central targets in the treatment of type 2 diabetes and obesity. The processes of downregulation and desensitisation that follow receptor activation directly influence a drug's sustained efficacy and clinical profile, and different agonist classes display striking differences in how they drive these events. Understanding the molecular basis of these differences is essential for optimising existing therapies and designing the next generation of incretin-based drugs.

Receptor internalisation is the central event in desensitisation. The classical view holds that a G protein-coupled receptor (GPCR), once activated by an agonist, is phosphorylated by G protein-coupled receptor kinases (GRKs), which then recruit β-arrestin; β-arrestin mediates internalisation and terminates G protein signalling. GLP-1R, however, follows an atypical regulatory pattern: its internalisation does not depend on β-arrestin. Studies show that even when β-arrestin is knocked out, agonist-induced internalisation of GLP-1R still occurs, although the process does require GRK activity. By contrast, GIPR internalisation depends entirely on β-arrestin recruitment. The two receptors therefore differ fundamentally at the molecular level.

Agonist classes differ markedly in how efficiently they drive GLP-1R internalisation. Native GLP-1, exendin-4, and liraglutide all rapidly induce receptor internalisation with similar kinetics, but the rate at which the receptor recycles back to the surface differs: recycling after liraglutide and exendin-4 is slower than after native GLP-1. More important findings come from biased agonists. Exendin-Phe1, a G protein-biased agonist, fully activates cAMP signalling while substantially reducing β-arrestin recruitment and internalisation. This "signalling preserved, internalisation diminished" property translates directly into more sustained insulin secretion from β cells.

Tirzepatide, a dual GLP-1/GIP receptor agonist, has an even more complex pharmacological profile. Its affinity for GIPR is comparable to that of native GIP, but its affinity for GLP-1R is roughly five times weaker, giving it an "unbalanced" bias toward GIPR. At the GLP-1R level, tirzepatide favours cAMP production over β-arrestin recruitment, and its ability to drive GLP-1R internalisation is weaker than that of native GLP-1. A 2021 study further confirmed that tirzepatide and another dual agonist, MAR709, display a distinctive spatiotemporal signalling pattern at both target receptors—"preserved maximal cAMP generation, accompanied by partial Gαs recruitment and reduced receptor internalisation." This bias not only shapes intracellular signalling but also uniquely modulates receptor trafficking fate.

GIPR regulation contrasts sharply with that of GLP-1R. In pancreatic β cells, GIPR internalisation and degradation are markedly lower than those of GLP-1R, while plasma membrane recycling is faster. This "slow internalisation, fast recycling" pattern allows GIPR to maintain a persistently high surface presence. GIPR desensitisation, however, is clearly cell-type dependent. In adipocytes and neuronal cells, prolonged GIPR agonism leads to receptor desensitisation, whereas this is not pronounced in pancreatic β cells—possibly related to differences in GIPR expression levels across cell types.

The clinical consequences of receptor desensitisation are not negligible. Sustained GLP-1R activation can cause receptor downregulation and thereby affect salivary gland function, which may explain the dry mouth and other oral side effects associated with semaglutide. GIPR desensitisation has been linked to insulin resistance and to the phenomenon of GIP resistance in type 2 diabetes. Notably, the E354Q variant of GIPR—a natural variant associated with increased insulin resistance and cardiovascular risk—shows faster internalisation and slower resensitisation, resulting in long-term receptor desensitisation.

Different agonist classes stabilise distinct conformational states of the receptor, directing it toward divergent internalisation and recycling pathways. G protein-biased agonists such as exendin-Phe1 and tirzepatide prolong plasma membrane cAMP signalling by attenuating β-arrestin recruitment and internalisation. This "bias" is not merely a choice of signalling pathway but a choice of receptor trafficking fate. As understanding of spatiotemporal signalling and trafficking control of incretin receptors deepens, rationally designing agonist bias to optimise the internalisation–recycling balance will become an important strategy for improving efficacy and reducing tolerance.