A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes

Abstract

The pancreatic islets are composed of discrete hormone producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of β cells using a single-cell transcriptomic approach. One subset of β cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibit higher mitochondrial respiration compared to CD63lo β cells. Human and murine pseudo-islets derived from CD63hi β cells demonstrate enhanced glucose-stimulated insulin secretion compared to pseudo-islets from CD63lo β cells. We show that CD63hi β cells are diminished in mouse models of and in humans with type 2 diabetes. Finally, transplantation of pseudo-islets generated from CD63hi but not CD63lo β cells into diabetic mice restores glucose homeostasis. These findings suggest that loss of a specific subset of β cells may lead to diabetes. Strategies to reconstitute or maintain CD63hi β cells may represent a potential anti-diabetic therapy.