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

ABSTRACT: Stem cell-derived ? (SC-?) cells could provide unlimited human ? cells toward a curative diabetes treatment. Differentiation of SC-? cells yields transplantable islets that secrete insulin in response to glucose challenges. Following transplantation into mice, SC-? 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-? 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-? cells. This activity can be rescued by challenging SC-? 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.

SUBMITTER: Davis JC 

PROVIDER: S-EPMC7433758 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature