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Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes
- Source :
- Nature Metabolism, Nat. Metab. 3, 1017–1031 (2021)
- Publication Year :
- 2021
-
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. Wigger, Barovic and Brunner et al. perform a multidimensional analysis of islets from metabolically characterized patients who had undergone pancreatectomy, observing remarkable heterogeneity between samples from individuals with type 2 diabetes, thus arguing against models of linear beta-cell dedifferentiation in diabetes.
- Subjects :
- Blood Glucose
Proteomics
endocrine system
endocrine system diseases
Lipide, Typ-2-Diabetes (T2D), Pankreasinseln, Multi-omics-Analyse
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
030209 endocrinology & metabolism
Type 2 diabetes
Biology
Impaired glucose tolerance
Islets of Langerhans
03 medical and health sciences
0302 clinical medicine
Insulin-Secreting Cells
Physiology (medical)
Diabetes mellitus
Living Donors
Internal Medicine
medicine
Humans
Insulin
Metabolomics
ddc:610
030304 developmental biology
0303 health sciences
geography
geography.geographical_feature_category
Gene Expression Profiling
Pancreatic islets
Transdifferentiation
lipids, type 2 diabetes (T2D), pancreatic islets, multi-omics analysis
Cell Biology
Islet
medicine.disease
medicine.anatomical_structure
Diabetes Mellitus, Type 2
Gene Expression Regulation
Pancreatectomy
Cancer research
Disease Susceptibility
Beta cell
Energy Metabolism
Biomarkers
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Nature Metabolism, Nat. Metab. 3, 1017–1031 (2021)
- Accession number :
- edsair.doi.dedup.....5a0a2de893c0f7383454822394989fff