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

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.

Dysfunction of Persisting ß Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis.

Type 2 diabetes is characterized by peripheral insulin resistance and insufficient insulin release from pancreatic islet ß cells. However, the role and sequence of ß cell dysfunction and mass loss for reduced insulin levels in type 2 diabetes pathogenesis are unclear. Here, we exploit freshly explanted pancreas specimens from metabolically phenotyped surgical patients using an in situ tissue slice technology. This approach allows assessment of ß cell volume and function within pancreas samples of metabolically stratified individuals. We show that, in tissue of pre-diabetic, impaired glucose-tolerant subjects, ß cell volume is unchanged, but function significantly deteriorates, exhibiting increased basal release and loss of first-phase insulin secretion. In individuals with type 2 diabetes, function within the sustained ß cell volume further declines. These results indicate that dysfunction of persisting ß cells is a key factor in the early development and progression of type 2 diabetes, representing a major target for diabetes prevention and therapy.

Metabolically phenotyped pancreatectomized patients as living donors for the study of islets in health and diabetes.

BACKGROUND: The availability of human pancreatic islets with characteristics closely resembling those present in vivo is instrumental for ex vivo studies in diabetes research. SCOPE OF REVIEW: In this review we propose metabolically phenotyped surgical patients as a novel source of pancreatic tissue for islet research. Laser Capture Microdissection from snap frozen surgical specimens is a relatively simple, reproducible and scalable method to isolate islets of highest purity for many types of "omics" analyses. Fresh pancreatic tissue slices enable the functional characterization of living islet cells in situ through dynamic experiments. Access to complete medical history and laboratory values for each donor offers the opportunity of direct correlations with different "omics" data and detailed metabolic profiling prior to pancreas surgery. Peripheral blood samples complete the picture of each patient and represent a platform for pursuit of biomarkers with uniquely comprehensive background information in regard to the donor's islet cells. MAJOR CONCLUSIONS: Living donors provide the scientific community with a steady and abundant supply of excellent material to study islets closest to their in situ environment, thus advancing our understanding of their physiology in health and diseases.