Phosphoproteomics Reveals the GSK3-PDX1 Axis as a Key Pathogenic Signaling Node in Diabetic Islets

• Published in: Cell metabolism 2019-06, Vol.29 (6), p.1422-1432.e3
• Main Authors: Sacco, Francesca, Seelig, Anett, Humphrey, Sean J., Krahmer, Natalie, Volta, Francesco, Reggio, Alessio, Marchetti, Piero, Gerdes, Jantje, Mann, Matthias
• Format: Article
• Language: English
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2019.02.012

Progressive decline of pancreatic beta cell function is central to the pathogenesis of type 2 diabetes. Protein phosphorylation regulates glucose-stimulated insulin secretion from beta cells, but how signaling networks are remodeled in diabetic islets in vivo remains unknown. Using high-sensitivity mass spectrometry-based proteomics, we quantified 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls, revealing drastic remodeling of key kinase hubs and signaling pathways. Integration with a literature-derived signaling network implicated GSK3 kinase in the control of the beta cell-specific transcription factor PDX1. Deep phosphoproteomic analysis of human islets chronically treated with high glucose demonstrated a conserved glucotoxicity-dependent role of GSK3 kinase in regulating insulin secretion. Remarkably, the ability of beta cells to secrete insulin in response to glucose was rescued almost completely by pharmacological inhibition of GSK3. Thus, our resource enables investigation of mechanisms and drug targets in type 2 diabetes. [Display omitted] •Pathogenic signaling pathways are rewired in type 2 diabetic islets•The GSK3-PDX1 axis is compromised in type 2 diabetic islets•The GSK3 kinase is a crucial regulator of GLUT2 and insulin expression•GSK3 inhibition restores the ability of diabetic islets to secrete insulin Using highly sensitive and streamlined mass spectrometry analyses, combined with bioinformatics, Sacco et al. generated in-depth proteome and phosphoproteome signaling network maps of normal and diabetic murine pancreatic islets. They identified GSK3 as a crucial regulatory node in insulin secretion; GSK3 inhibition restores the ability of diabetic islets to secrete insulin.