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

Mol Metab. 2020 Dec;42:101057. doi: 10.1016/j.molmet.2020.101057. Epub 2020 Jul 30.


Objective: Dedifferentiation of pancreatic β-cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown.

Methods: We employed single-cell RNAseq to detail the maturation program of α- and β-cells during human ontogeny. We also compared islets from non-diabetic and T2D individuals.

Results: Both α- and β-cells mature in part by repressing non-endocrine genes; however, α-cells retain hallmarks of an immature state, while β-cells attain a full β-cell specific gene expression program. In islets from T2D donors, both α- and β-cells have a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes and increasing expression of exocytosis, inflammation and stress response signalling pathways. These changes are consistent with the increased proportion of β-cells displaying suboptimal function observed in T2D islets.

Conclusions: These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.

Keywords: Human islet; Ontogeny; Single cell RNAseq; Type 2 diabetes; α-Cell; β-Cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Dedifferentiation / genetics*
  • Cell Dedifferentiation / physiology
  • Computational Biology / methods
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Exocytosis / physiology
  • Gene Expression / genetics
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / genetics
  • Glucagon-Secreting Cells / metabolism
  • Glucagon-Secreting Cells / physiology
  • Humans
  • Inflammation / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / physiology
  • Islets of Langerhans / metabolism
  • Pancreas / metabolism
  • Primary Cell Culture
  • Signal Transduction / physiology
  • Single-Cell Analysis / methods
  • Transcriptome / genetics