Decoding pancreatic islet cell diversity through cell type-resolved proteomics and phosphoproteomics

Islets of Langerhans are micro-organs scattered throughout the pancreas. They are composed of insulin-producing beta cells, glucagon-producing alpha cells, and somatostatin-producing delta cells. While their transcriptome has been extensively analyzed, protein-level information remains limited due to cell scarcity and purification challenges. Here, we combine cell sorting with highly sensitive mass spectrometry to create the first in depth proteomic atlas of pancreatic islet cells. We achieved a depth exceeding 6,000 proteins per endocrine cell population, discovering new cell type-enriched ones. Deep proteomics profiling upon interferon gamma (IFNγ) treatment, mimicking inflammation in type 1 diabetes demonstrated that all three endocrine cell types were inflamed upon IFNγ stimulation. Resolving the phosphoproteomic landscape of alpha, beta and delta cells with more than 7,000 unique phosphosites per cell type provided insights into cell-specific signaling. This multi-omics atlas offers a valuable resource for understanding pancreatic islet biology in health and disease.