Nat Metab.: co-auth.: B.Thorens

Nat Metab. 2021 Jun 28. doi: 10.1038/s42255-021-00420-9. Online ahead of print.

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes

Leonore Wigger # 1Marko Barovic # 2 3 4Andreas-David Brunner # 5Flavia Marzetta 1Eyke Schöniger 2 3 4Florence Mehl 1Nicole Kipke 2 3 4Daniela Friedland 2 3 4Frederic Burdet 1Camille Kessler 1Mathias Lesche 6Bernard Thorens 7Ezio Bonifacio 3 4 8Cristina Legido-Quigley 9 10Pierre Barbier Saint Hilaire 11Philippe Delerive 12Andreas Dahl 6Christian Klose 13Mathias J Gerl 13Kai Simons 13Daniela Aust 14 15Jürgen Weitz 16Marius Distler 16Anke M Schulte 17Matthias Mann 18Mark Ibberson 19Michele Solimena 20 21 22


Most research on human pancreatic islets is conducted on samples obtained from normoglycaemic or diseased brain-dead donors and thus cannot accurately describe the molecular changes of pancreatic islet beta cells as they progress towards a state of deficient insulin secretion in type 2 diabetes (T2D). Here, we conduct a comprehensive multi-omics analysis of pancreatic islets obtained from metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum, from normoglycemia to T2D. We find that islet pools isolated from surgical samples by laser-capture microdissection display remarkably more heterogeneous transcriptomic and proteomic profiles in patients with diabetes than in non-diabetic controls. The differential regulation of islet gene expression is already observed in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive, but disharmonic, remodelling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or transdifferentiation stages in T2D. Furthermore, through integration of islet transcriptomics with preoperative blood plasma lipidomics, we define the relative importance of gene coexpression modules and lipids that are positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.