Glucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in Glycolysis

Jeffrey C. Davis, Tiago C. Alves, Aharon Helman, Jonathan C. Chen, Jennifer H. Kenty, Rebecca L. Cardone, David R. Liu, Richard G. Kibbey, Douglas A. Melton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Stem cell-derived β (SC-β) cells could provide unlimited human β cells toward a curative diabetes treatment. Differentiation of SC-β cells yields transplantable islets that secrete insulin in response to glucose challenges. Following transplantation into mice, SC-β cell function is comparable to human islets, but the magnitude and consistency of response in vitro are less robust than observed in cadaveric islets. Here, we profile metabolism of SC-β cells and islets to quantify their capacity to sense glucose and identify reduced anaplerotic cycling in the mitochondria as the cause of reduced glucose-stimulated insulin secretion in SC-β cells. This activity can be rescued by challenging SC-β cells with intermediate metabolites from the TCA cycle and late but not early glycolysis, downstream of the enzymes glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate kinase. Bypassing this metabolic bottleneck results in a robust, bi-phasic insulin release in vitro that is identical in magnitude to functionally mature human islets.

Original languageAmerican English
Article number107623
JournalCell Reports
Volume31
Issue number6
DOIs
StatePublished - 12 May 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • GSIS
  • MIMOSA
  • differentiation
  • glucose-stimulated insulin secretion
  • metabolic profiling
  • stem cell metabolism
  • stem cell-derived β cell
  • β-cell metabolism

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