A Cross-Species Subcellular Proteomic Atlas Reveals Pancreatic Islet Cytoarchitecture and Remodeling in Type 2 Diabetes

ABSTRACT: The unique cytoarchitecture of pancreatic β-cells is key for their role as glucose sensors and endocrine regulators, enabling precise insulin secretion to maintain blood glucose within a narrow physiological range. The dysfunction of β-cells is a hallmark of type 2 diabetes (T2D), yet, despite the clinical importance, the underlying mechanisms remain incompletely understood. To address this, we employed proteomic organelle profiling combined with machine learning–based localization mapping to generate a comprehensive subcellular atlas of pancreatic islets from humans, mice, and pigs. As β-cells are the predominant cell type in islets, the resulting maps primarily reflect β-cell organization and include subcellular and organelle localization data for over 8,000 proteins. Cross-species comparisons revealed conserved features of organelle architecture, previously uncharacterized insulin granule proteins, and species-specific differences in key pathways relevant to β-cell function. Using a T2D mouse model, we further investigated disease-related alterations in β-cell organization. We identified novel insulin granule proteins and observed a reorganization of phosphoinositide signaling, disruption of vesicular trafficking, disassembly of the insulin granule acidification machinery, and reprogramming of mitochondrial amino acid metabolism. Together, our atlas provides a high-resolution in vivo blueprint of pancreatic islet cell architecture and uncovers key processes contributing to β-cell failure in T2D. Key points • We provide a cross-species pancreatic islet proteomic subcellular atlas • Cytoarchitecture is more conserved in human and pig than mice • Phosphoinositide signaling and vesicular trafficking reorganize in T2D • Insulin granule acidification machinery disassembles in T2D • Mitochondria increase proline synthesis machinery in T2D • NHLRC33 is a conserved yet unknown insulin granule protein

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Sus Scrofa Domesticus (domestic Pig) Mus Musculus (mouse)

TISSUE(S): Pancreatic Islet, Type B Pancreatic Cell

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Natalie Krahmer  

LAB HEAD: Natalie Krahmer

PROVIDER: PXD064528 | Pride | 2026-06-29

REPOSITORIES: Pride