Pancreatic islets, in which β cells constitute 50%–80% of the endocrine
mass, are the body’s site for glucose-regulated insulin secretion.
Pancreatic islet dysfunction is a hallmark of type 2 diabetes.
Nevertheless, the molecular changes that impair their function remain
insufficiently understood. To determine how islet cellular organization
supports function and how it deteriorates in disease, we used machine
learning-based organelle proteomics to build an organelle atlas of
pancreatic islets from mice, humans, and pig neonatal islet-like cells.
This cross-species resource maps localization of ∼8,000 proteins,
revealing conserved organelle organization and identifying previously
unrecognized components of insulin granules. Applying our organelle
proteomics workflow to db/db mice, a T2D model uncovered
disease-associated changes affecting vesicular trafficking and
mitochondrial amino acid metabolism. Additionally, we found a
disassembly of the insulin-granule acidification machinery. Our atlas
provides insights into islet subcellular organization and identifies
processes whose disruption may drive pancreatic islet failure in T2D.
FörderungenGerman Research Foundation European Research Council ERC-CoG Helmholtz Association-Initiative and Networking Fund International Helmholtz Research School for Diabetes European Foundation for the Study of Diabetes (Future Leader Award) DFG Emmy Noether