Proteomics

Dataset Information

25

Phosphoproteomics reveals the GSK3-PDX1 axis as a key pathogenic signaling node in diabetic islets


ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus musculus   Homo sapiens  

TISSUE(S): Pancreas

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Natalie Krahmer  

LAB HEAD: Matthias Mann

PROVIDER: PXD012671 | Pride | 2019-03-15

REPOSITORIES: Pride

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