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.
GrantsDFG Emmy Noether European Foundation for the Study of Diabetes (Future Leader Award) International Helmholtz Research School for Diabetes Helmholtz Association-Initiative and Networking Fund European Research Council ERC-CoG German Research Foundation