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Interestingly, despite the lack of metabolic consequence in hepatocyte RAMP2-overexpressing mice, hepatocyte-specific knockdown of the endosomal protein VPS37a within in vitro and ex vivo settings increases ligand-bound GcgR localization into G s accessible endosomes, enhances total G s /cAMP signaling, reduces lysosomal targeting, and alters endosomal localization which when applied in vivo significantly upregulates glucose production and biases hepatic metabolic flux away from fatty acid oxidation [164]

An increase in the incidence of cardiac arrhythmias, mainly supraventricular, was noted in some trial arms