Matches in SemOpenAlex for { <https://semopenalex.org/work/W3134896487> ?p ?o ?g. }
- W3134896487 endingPage "101242" @default.
- W3134896487 startingPage "101242" @default.
- W3134896487 abstract "Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study, we investigated the cellular and metabolic effects of modulating the balance between G protein and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation.Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify the effects on glucose homeostasis and weight loss.Ligand-specific reductions in β-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide despite a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured.Diminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism." @default.
- W3134896487 created "2021-03-15" @default.
- W3134896487 creator A5005229009 @default.
- W3134896487 creator A5011477177 @default.
- W3134896487 creator A5014892318 @default.
- W3134896487 creator A5027432256 @default.
- W3134896487 creator A5031282682 @default.
- W3134896487 creator A5032705747 @default.
- W3134896487 creator A5039639796 @default.
- W3134896487 creator A5039784437 @default.
- W3134896487 creator A5055696357 @default.
- W3134896487 creator A5070912983 @default.
- W3134896487 creator A5078917204 @default.
- W3134896487 creator A5082783884 @default.
- W3134896487 creator A5086104178 @default.
- W3134896487 creator A5087842003 @default.
- W3134896487 creator A5089203690 @default.
- W3134896487 date "2021-09-01" @default.
- W3134896487 modified "2023-10-06" @default.
- W3134896487 title "Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist" @default.
- W3134896487 cites W1798757189 @default.
- W3134896487 cites W1971748110 @default.
- W3134896487 cites W1976676978 @default.
- W3134896487 cites W1987856394 @default.
- W3134896487 cites W1993582432 @default.
- W3134896487 cites W1994319147 @default.
- W3134896487 cites W1998666715 @default.
- W3134896487 cites W2009199589 @default.
- W3134896487 cites W2023595800 @default.
- W3134896487 cites W2042765505 @default.
- W3134896487 cites W2047944726 @default.
- W3134896487 cites W2056594490 @default.
- W3134896487 cites W2120041117 @default.
- W3134896487 cites W2121558006 @default.
- W3134896487 cites W2122188063 @default.
- W3134896487 cites W2132295069 @default.
- W3134896487 cites W2138325877 @default.
- W3134896487 cites W2148623180 @default.
- W3134896487 cites W2153134360 @default.
- W3134896487 cites W2154319440 @default.
- W3134896487 cites W2162140339 @default.
- W3134896487 cites W2168899316 @default.
- W3134896487 cites W2184351123 @default.
- W3134896487 cites W2226712470 @default.
- W3134896487 cites W2252989708 @default.
- W3134896487 cites W2294268013 @default.
- W3134896487 cites W2319292032 @default.
- W3134896487 cites W2336523804 @default.
- W3134896487 cites W2419951851 @default.
- W3134896487 cites W2464238397 @default.
- W3134896487 cites W2512819857 @default.
- W3134896487 cites W2519031788 @default.
- W3134896487 cites W2568027424 @default.
- W3134896487 cites W2600127085 @default.
- W3134896487 cites W2622192206 @default.
- W3134896487 cites W2635189679 @default.
- W3134896487 cites W2718966341 @default.
- W3134896487 cites W2730889053 @default.
- W3134896487 cites W2770319189 @default.
- W3134896487 cites W2782378357 @default.
- W3134896487 cites W2783056392 @default.
- W3134896487 cites W2783806692 @default.
- W3134896487 cites W2784321341 @default.
- W3134896487 cites W2790112182 @default.
- W3134896487 cites W2791680789 @default.
- W3134896487 cites W2800843957 @default.
- W3134896487 cites W2802400646 @default.
- W3134896487 cites W2808958607 @default.
- W3134896487 cites W2886911834 @default.
- W3134896487 cites W2889408384 @default.
- W3134896487 cites W2892037130 @default.
- W3134896487 cites W2899339394 @default.
- W3134896487 cites W2924479779 @default.
- W3134896487 cites W2969232909 @default.
- W3134896487 cites W2973135310 @default.
- W3134896487 cites W2987056370 @default.
- W3134896487 cites W3002178166 @default.
- W3134896487 cites W3012065601 @default.
- W3134896487 cites W3012148265 @default.
- W3134896487 cites W3015123576 @default.
- W3134896487 cites W3016119493 @default.
- W3134896487 cites W3021215520 @default.
- W3134896487 cites W3022830342 @default.
- W3134896487 cites W3041548136 @default.
- W3134896487 cites W3042820553 @default.
- W3134896487 cites W3045242905 @default.
- W3134896487 cites W3045729180 @default.
- W3134896487 cites W3049413675 @default.
- W3134896487 cites W3099310113 @default.
- W3134896487 cites W3127014820 @default.
- W3134896487 cites W4211232835 @default.
- W3134896487 doi "https://doi.org/10.1016/j.molmet.2021.101242" @default.
- W3134896487 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8163982" @default.
- W3134896487 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33933675" @default.
- W3134896487 hasPublicationYear "2021" @default.
- W3134896487 type Work @default.
- W3134896487 sameAs 3134896487 @default.
- W3134896487 citedByCount "7" @default.