The Journal of biological chemistryDec 3, 2020

Genetic changes and selective drugs that reduce β-arrestin increase cAMP signals at glucagon-related receptors

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 1, 2026

Abstract

GLP-1, GIP, and GCGR agonists with reduced β-arrestin-2 recruitment may improve insulin secretion.

GLP-1R, GIPR, and GCGR regulate insulin secretion and energy metabolism.
Reducing β-arrestin-2 recruitment in GLP-1R agonists has led to promising results in previous studies.
In cells lacking both β-arrestin isoforms, cAMP/PKA signaling duration increased in response to the receptors' endogenous ligands.
Biased GLP-1, GCG, and GIP analogs showed reduced receptor endocytosis and increased insulin secretion at high concentrations.
Biased GCG analogs prolonged cAMP signaling duration without increasing glucose output from liver cells.
Further research is required to optimize agonists targeting GLP-1R, GIPR, and GCGR for therapeutic applications.

Simplified

Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitization and downregulation due to recruitment of β-arrestins. Indeed, recently described GLP-1R agonists with reduced β-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both β-arrestin isoforms the duration of G protein-dependent cAMP/PKA signaling was increased in response to the endogenous ligand for each receptor. Moreover, in wildtype cells, "biased" GLP-1, GCG, and GIP analogs with selective reductions in β-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogs increased the duration of cAMP signaling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for the development of GLP-1R, GIPR, and GCGR agonists with reduced β-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.

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Competing interests

Conflict of interest G. A. R. is a consultant for Sun Pharmaceuticals and has received grant funding from Sun Pharmaceuticals and Les Laboratoires Servier. B. J. and A. T. have received grant funding from Sun Pharmaceuticals.

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Genetic changes and selective drugs that reduce β-arrestin increase cAMP signals at glucagon-related receptors

Abstract

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