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However, in keeping with our data on receptor pharmacology, increasing the dose to 30 nmol kg 1 , tenfold higher than maximal doses from our studies, shows that tirzepatide does have insulinotropic activity in Glp1r -/- mice or in the presence of a GLP-1R antagonist 5 , demonstrating that tirzepatide can engage the GIPR in mouse beta cells at sufficiently high concentrations

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However, long-term use is associated with challenges such as motor fluctuations, dyskinesias, and loss of therapeutic efficacy due to progressive neurodegeneration and alterations in dopaminergic pathways