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

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