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

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