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

doi:10.1016/j.celrep.2020.107623

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.

Authors

Jeffrey C Davis¹, Tiago C Alves², Aharon Helman¹, Jonathan C Chen³, Jennifer H Kenty¹, Rebecca L Cardone⁴, David R Liu⁵, Richard G Kibbey⁶, Douglas A Melton⁷

Affiliations

¹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
² Department of Internal Medicine (Endocrinology), Yale University, New Haven, CT, USA; Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
³ Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁴ Department of Internal Medicine (Endocrinology), Yale University, New Haven, CT, USA.
⁵ Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁶ Department of Internal Medicine (Endocrinology), Yale University, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA.
⁷ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: dmelton@harvard.edu.

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.

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*

Substances

Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding