Hormonal
GLP-1 receptor agonists that reduce receptor internalization and beta-arrestin recruitment produce greater sustained insulin secretion and glycemic benefits without increasing nausea side effects compared to standard FDA-approved GLP-1 mimetics.
Current GLP-1 drugs often cause nausea because they trigger strong receptor internalization and beta-arrestin signaling. Research suggests that 'biased' agonists, which keep the receptor on the cell surface longer and avoid beta-arrestin, may provide better blood sugar control with fewer stomach side effects. While these specific compounds are not yet FDA-approved, the mechanism highlights why tolerability varies between different GLP-1 medications.
Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies.
Why this rating
Strong mechanistic data in cell lines and mouse models, but lacks human clinical trial data.
Source
Targeting GLP-1 receptor trafficking to improve agonist efficacy
Ben Jones et al. · Nature Communications · 2018
DOI 10.1038/s41467-018-03941-2
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