Incretin signaling and, in particular, its effect on signaling bias may lead to the development of novel incretin agonists with the potential to produce weight loss and glycemic control for people with obesity and diabetes.
Both the GLP-1 and GIP receptors belong to the class of receptors called G protein-coupled receptors (GPCRs). When GLP-1 or GIP binds to its respective receptor it causes the receptor to change shape, which results in the activation of the G protein complex and subsequent signaling pathway. In the case of both GLP-1 and GIP, binding with their respective receptors results in the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway. ß-arrestin is also recruited to the receptor upon activation, which then diminishes the G protein signaling, partially through receptor trafficking. Carmot studies have shown that a biased GLP-1 receptor agonist that activates cAMP with minimal to no ß-arrestin recruitment resulted in prolonged glucose lowering and weight loss.
To maximize the therapeutic window of incretin agonists, Carmot designed them with signaling bias to preferentially activate cAMP while having minimal to no ß-arrestin recruitment. This results in decreased receptor internalization (endocytosis) and desensitization, both of which may lead to prolonged pharmacological activity.