Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets
Tom Barsby,
Eliisa Vähäkangas,
Jarkko Ustinov,
Hossam Montaser,
Hazem Ibrahim,
Väinö Lithovius,
Emilia Kuuluvainen,
Vikash Chandra,
Jonna Saarimäki-Vire,
Pekka Katajisto,
Ville Hietakangas,
Timo Otonkoski
Affiliations
Tom Barsby
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Corresponding author
Eliisa Vähäkangas
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Jarkko Ustinov
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Hossam Montaser
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Hazem Ibrahim
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Väinö Lithovius
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Emilia Kuuluvainen
Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
Vikash Chandra
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Jonna Saarimäki-Vire
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Pekka Katajisto
Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
Ville Hietakangas
Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
Timo Otonkoski
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Children’s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Corresponding author
Summary: 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.
