title: Single-cell transcriptomes identify human islet cell signatures and reveal cell-type-specific expression changes in type 2 diabetes.
abstract: Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type-specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis.
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
authors.forename: Nathan
authors.identifier: 0000-0003-3263-6057
authors.initials: N
authors.lastname: Lawlor
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
authors.forename: Joshy
authors.identifier: 0000-0001-8510-8229
authors.initials: J
authors.lastname: George
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
authors.forename: Mohan
authors.initials: M
authors.lastname: Bolisetty
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
authors.forename: Romy
authors.initials: R
authors.lastname: Kursawe
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Sun
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
authors.forename: V
authors.initials: V
authors.lastname: Sivakamasundari
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.
authors.forename: Ina
authors.initials: I
authors.lastname: Kycia
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.|Institute for Systems Genomics, University of Connecticut, Farmington, Connecticut 06032, USA.|Department of Genetics & Genome Sciences, University of Connecticut, Farmington, Connecticut 06032, USA.
authors.forename: Paul
authors.identifier: 0000-0002-0191-3958
authors.initials: P
authors.lastname: Robson
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA.|Institute for Systems Genomics, University of Connecticut, Farmington, Connecticut 06032, USA.|Department of Genetics & Genome Sciences, University of Connecticut, Farmington, Connecticut 06032, USA.
authors.forename: Michael L
authors.identifier: 0000-0001-5630-559X
authors.initials: ML
authors.lastname: Stitzel
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D059010:Single-Cell Analysis; D059467:Transcriptome / Q000235:genetics*
chemical_list: D002352:Carrier Proteins