ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 65 P235 | DOI: 10.1530/endoabs.65.P235

Insights into the mechanisms underpinning the physiological effects of biased GLP-1 receptor agonists

Maria Lucey1, Phil Pickford1, Yue Ma1, Maria Shchepinova1, Ed Tate1, James McGinty1, Paul French1, Samuel Davies1, Gabriela Da Silva Xavier2, Emilie Stolarczyk1, James Minnion1, Guy Rutter1, Steve Bloom1, Alejandra Tomas1 & Ben Jones1

1Imperial College London, London, UK; 2University of Birmingham, Birmingham, UK

Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective treatments for type 2 diabetes and obesity. We recently described ‘biased’ peptide GLP-1R agonists modelled on exendin-4 which uncouple the pronounced endocytosis that usually accompanies GLP-1R activation, leading to prolongation of intracellular signalling responses. Here, we show that the metabolic consequences of biased GLP-1R activation in vivo are dominated by improvements in blood glucose, without concomitant increases in their anorectic properties (40-fold relative preference for glycaemic vs. anorectic effects). To investigate this disparity, we have compared cell type-specific responses to biased GLP-1R agonists using in vitro beta cell and neuronal models, in case the downstream manifestations of bias differ according to the tissue in which they act. We also delivered these ligands directly into the CNS in mice to bypass the blood-brain-barrier, under which circumstances the anticipated efficacy increase of the biased agonist was restored. Biodistribution studies using the same compounds conjugated to near-infrared fluorophores, which allow deep tissue imaging of optically cleared intact brain and pancreas specimens, have also provided a means to assess whether biased ligands have equal or differential access to appetite regulatory centres in the CNS.