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 language | English |
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Article number | 107623 |
Journal | Cell Reports |
Volume | 31 |
Issue number | 6 |
DOIs | |
State | Published - 12 May 2020 |
Externally published | Yes |
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