biostudies-literatureAustin GNIDDK NIH HHSMedical Research CouncilDiabetes UKWellcome TrustBiotechnology and Biological Sciences Research Council11010https://www.ebi.ac.uk/biostudies/studies/S-EPMC12696101biostudies-literatureUnknown16(1)Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and β-cell functional adaptation. Here, we present a comprehensive study in β-cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticNature communicationsGLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.PMC12696101227745/Z/23/Z104931/Z/14/ZMR/X021467/1301619/Z/23/ZBB/L015129/1UC4 DK09808519/0006094Balkhiyarova ZBouzakri KGaboriau DCAManchanda YTomas AOqua AICoyle HWithers DJJones BMillership SJZhu MMajorovits EBurgold SGarlick EProkopenko IMuller AAustin GEl Eid LPeres PSolimena MMontoya APoliakova Ydo R B F Lima MANixon-Abell JfalseGLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and β-cell functional adaptation. Here, we present a comprehensive study in β-cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic retic2025-01-01T00:00:00Z2025 Dec2026-06-06T03:55:21.679Z2026-05-25T03:12:00.445ZS-EPMC126961014137212210.1038/s41467-025-66115-x