1711-P: Pancreas Single-Cell Patch-Seq Links Physiologic Dysfunction in Diabetes to Transcriptomic Phenotypes

Abstract

Pancreatic islet-cells regulate glucose levels in the body through insulin and glucagon secretion; dysfunction of these cells leads to severe disease such as diabetes. Several single-cell transcriptome studies have shown heterogeneous gene expression in major islet cell-types such as beta and alpha cells. However, it has remained an open challenge to reconcile the heterogeneity in transcriptomic signatures with physiological observations of functional heterogeneity. Here we combined electrophysiological profiling and single-cell RNA sequencing of the same cells (pancreas patch-seq) to link transcriptomic phenotypes of islet cells to their physiologic properties. We collected 1,369 pancreas patch-seq cells from fresh and cryopreserved tissue and assessed function-gene expression networks in nondiabetic, type 1 diabetic (T1D) and type 2 diabetic (T2D) humans. We discovered that ‘hub’ genes and pathways drive functional heterogeneity in nondiabetic beta-cells and show that specific transcriptional programs correlate with physiologic dysfunction early in T2D. We have also found evidence that alpha-cell transcriptional plasticity acts as a driver of dysfunction in T1D. Disclosure J. Camunas Soler: None. X. Dai: None. Y. Hang: None. S. Kim: None. P. MacDonald: None. Funding Chan Zuckerberg Biohub; California Institute for Regenerative Medicine; National Institutes of Health

Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D

“…In addition to the activation of genes normally expressed in newborn and non-β-cells, our dataset shows increased expression of exocytosis genes important for insulin secretion in T2D β cells. These genes include TSPAN1 , recently identified as a positive regulator of β-cell exocytosis [ 78 ] and RGS16 , encoding a regulator of G-protein signalling, shown to stimulate insulin secretion and to be upregulated under hyperglycaemic conditions (both increased by 8 fold on average, Figure S2C ) [ 79 ]. Interestingly, G6PC2 , which limits insulin secretion at low glucose levels and is activated with age about 3-fold on average ( Figure 1 G), is downregulated in T2D back to the levels typical of young children (2-fold, Figure 4 G), which could impact glucose-stimulated insulin secretion.…”