Barsby Tom, Vähäkangas Eliisa, Ustinov Jarkko, Montaser Hossam, Ibrahim Hazem, Lithovius Väinö, Kuuluvainen Emilia, Chandra Vikash, Saarimäki-Vire Jonna, Katajisto Pekka, Hietakangas Ville, Otonkoski Timo
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Cell Rep. 2023 Aug 29;42(8):112970. doi: 10.1016/j.celrep.2023.112970. Epub 2023 Aug 8.
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 C-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.
胰岛通过胰岛素的受控释放来调节血糖稳态；然而，目前对葡萄糖敏感的胰岛素分泌的代谢模型并不完整。对胰岛代谢的全面理解对于内分泌细胞发育以及糖尿病胰岛功能障碍的研究至关重要。人多能干细胞衍生的胰岛（SC-胰岛）是一种与人类胰岛功能发育相关的模型，在为1型糖尿病提供治愈方法方面具有巨大潜力。使用多种C标记的代谢燃料，我们证明与原代人胰岛相比，SC-胰岛在拟议的胰岛素释放途径中显示出许多不同的代谢物转运模式，但仍依赖线粒体有氧代谢来发挥功能。此外，SC-胰岛中发生还原性三羧酸循环活性和糖酵解代谢物循环，表明也存在非经典偶联因子。总体而言，我们表明SC-胰岛代谢的许多方面与原代胰岛的代谢方面重叠，尽管保留了未成熟的特征。
