Biased incretin receptor signaling to improve metabolic efficacy
Andreas Birkenfeld & Timo Müller
Co-agonists at the receptors for glucagon-like peptide-1 (GLP-1R) and glucose- dependent insulinotropic polypeptide (GIPR) are in clinical trials for the treatment of obesity and diabetes. GLP-1R and GIPR signal via Gs and Gq/11 proteins but also recruit β-arrestin to signal via extracellular-signal regulated kinase 1/2 (ERK1/2). Despite binding to the same receptor, different GLP-1R ligands engage selective pathways to elicit different cellular responses. This "biased agonism" can be of great value, as certain ligands may strengthen specific pathways to optimize therapeutic outcome. Biased agonism was shown for exendin-4 and oxyntomodulin, which, relative to GLP-1, favor β-arrestin signaling. In rat insulinoma-1 (INS-1) cells, knockdown of β-arrestin attenuates GLP-1-stimulation of insulin secretion and decreases activation of ERK1/26. β-arrestin also promotes cell proliferation and survival via ERK1/2 signaling.
In this project we will assess whether selected GIPR and GLP-1R mono- and dual-agonists differ in receptor signaling, trafficking and recycling, whether ligands identified for biased agonism show enhanced in vivo effects to improve obesity and diabetes in mice with genetic- or diet-induced obesity and whether biased agonism translates to improved glucose, energy, and lipid metabolism in human organ-on-a-chip models comprising probes of human adipocytes, pancreatic islets and liver cells from male and female donors.