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

Cell Rep. 2020 May 12;31(6):107623. doi: 10.1016/j.celrep.2020.107623.


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.

Keywords: GSIS; MIMOSA; differentiation; glucose-stimulated insulin secretion; metabolic profiling; stem cell metabolism; stem cell-derived β cell; β-cell metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • Cell Differentiation
  • Glucose / metabolism*
  • Glycolysis / genetics*
  • Humans
  • Mice
  • Stem Cells / metabolism*


  • Glucose