Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets.

Pancreatic islets regulate blood glucose homeostasis through the controlled release of insulin; however, current metabolic models of glucose-sensitive insulin secretion are incomplete. A comprehensive understanding of islet metabolism is integral to studies of endocrine cell development as well as diabetic islet dysfunction. Human pluripotent stem cell-derived islets (SC-islets) are a developmentally relevant model of human islet function that have great potential in providing a cure for type 1 diabetes. Using multiple ¹³C-labeled metabolic fuels, we demonstrate that SC-islets show numerous divergent patterns of metabolite trafficking in proposed insulin release pathways compared with primary human islets but are still reliant on mitochondrial aerobic metabolism to derive function. Furthermore, reductive tricarboxylic acid cycle activity and glycolytic metabolite cycling occur in SC-islets, suggesting that non-canonical coupling factors are also present. In aggregate, we show that many facets of SC-islet metabolism overlap with those of primary islets, albeit with a retained immature signature. [Display omitted] • SC-islets show reduced glucose-derived cytosolic pathway metabolism • TCA cycle activity is essential for insulin secretion in SC-islets • SC-islets display aberrant directionality of mitochondrial metabolism • Non-canonical fuel-coupling pathways are present in SC-islets Stem cell-derived islets (SC-islets) represent the next generation of diabetes modeling and cell therapy development. In this study, Barsby et al. map the many points of metabolic divergence of SC-islets from primary tissue. These data will help progress the recapitulation of islet maturation necessary for the widespread use of SC-islets. [ABSTRACT FROM AUTHOR]