In vivo phosphoproteomics reveals pathogenic signaling changes in diabetic islets

SUMMARY Progressive decline of pancreatic beta cells function is key to the pathogenesis of type 2 diabetes. Protein phosphorylation is the central mechanism controlling glucose-stimulated insulin secretion in beta cells. However, if and how signaling networks are remodeled in diabetic islets in vivo remain unknowns. Here we applied high-sensitivity mass spectrometry-based proteomics and quantified the levels of about 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls. This highlighted drastic remodeling of key kinase hubs and signaling pathways. We integrated our phosphoproteomic dataset with a literature-derived signaling network, which revealed a crucial and conserved role of GSK3 kinase in the control of the beta cells-specific transcription factor PDX1 and insulin secretion, which we functionally verified. Our resource will enable the community to investigate potential mechanisms and drug targets in type 2 diabetes.