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Phosphoproteomics reveals the GSK3-PDX1 axis as a key pathogenic signaling node in diabetic islets.
Cell Metab. 29, 1422-1432.e3 (2019)
Publ. Version/Full Text
Preprint
Research data
DOI
PMC
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Pancreatic Beta-cells; Insulin-resistance; Type-2; Identification; Association; Dysfunction; Proteomics; Genetics; Obesity; Gsk-3
ISSN (print) / ISBN
1550-4131
e-ISSN
1932-7420
Journal
Cell Metabolism
Quellenangaben
Volume: 29,
Issue: 6,
Pages: 1422-1432.e3
Publisher
Elsevier
Publishing Place
50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
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Reviewing status
Peer reviewed