Metabolic Programming of β-Cell Fate, State, and Function through Time and Space

β-cells maintain glucose homeostasis by adjusting insulin secretion to meet the demands of (patho)physiological triggers; yet, they also undergo energy-dependent transitions between proliferation, differentiation, and maturation that underlie function across the lifespan. There are energy costs to prioritizing distinct cell states within β-cells. As such, specific metabolic programming is likely essential for distinct β-cell states as they toggle between immaturity and maturity. Transcriptional, nutritional, hormonal, and stress-based cues coordinately regulate the development of native β-cells in vivo. These steps are mirrored in protocols to differentiate human pluripotent stem cells (hPSCs) into β-like cells, but these cells remain functionally immature. Understanding how metabolic programs drive β-cell state transitions may reveal strategies to accelerate stem cell-derived (sc)-islet maturation, restore β-cell function in diabetes, and improve cell-based therapies. Here, we outline the known and unknown metabolic physiology of β-cells throughout development in vivo and in vitro.