@article{8e8c2d20797a4e508ba6469d70638c8d,
title = "Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes",
abstract = "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.",
keywords = "Biomarkers, Blood Glucose, Diabetes Mellitus, Type 2/etiology, Disease Susceptibility, Energy Metabolism, Gene Expression Profiling, Gene Expression Regulation, Humans, Insulin-Secreting Cells/metabolism, Insulin/metabolism, Islets of Langerhans/metabolism, Living Donors, Metabolomics, Proteomics",
author = "Leonore Wigger and Marko Barovic and Brunner, {Andreas David} and Flavia Marzetta and Eyke Sch{\"o}niger and Florence Mehl and Nicole Kipke and Daniela Friedland and Frederic Burdet and Camille Kessler and Mathias Lesche and Bernard Thorens and Ezio Bonifacio and Cristina Legido-Quigley and {Barbier Saint Hilaire}, Pierre and Philippe Delerive and Andreas Dahl and Christian Klose and Gerl, {Mathias J.} and Kai Simons and Daniela Aust and J{\"u}rgen Weitz and Marius Distler and Schulte, {Anke M.} and Matthias Mann and Mark Ibberson and Michele Solimena",
note = "Funding Information: We wish to thank L. Groop, E. Ahlqvist, S. Speier, T. Chavakis, R. Scharfmann and A. Schevchenko for discussion; S. Pradervand for advice on RNA-seq processing and QC; C. Rocher for Bioinformatics analysis support; K. Pfriem for administrative assistance. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115881 (RHAPSODY). This joint undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation program and EFPIA. This work is further supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 16.0097-2. Work in the Solimena lab is also supported with funds from the German Ministry of Education and Research to the German Center for Diabetes Research (DZD). The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = jul,
doi = "10.1038/s42255-021-00420-9",
language = "English",
volume = "3",
pages = "1017--1031",
journal = "Nature metabolism",
issn = "2522-5812",
publisher = "Springer Berlin",
number = "7",
}