Metabolic cycles and signals for insulin secretion

• Published in: Cell metabolism 2022-07, Vol.34 (7), p.947-968
• Main Authors: Merrins, Matthew J., Corkey, Barbara E., Kibbey, Richard G., Prentki, Marc
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Glucose - metabolism; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - metabolism
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2022.06.003

In this review, we focus on recent developments in our understanding of nutrient-induced insulin secretion that challenge a key aspect of the “canonical” model, in which an oxidative phosphorylation-driven rise in ATP production closes KATP channels. We discuss the importance of intrinsic β cell metabolic oscillations; the phasic alignment of relevant metabolic cycles, shuttles, and shunts; and how their temporal and compartmental relationships align with the triggering phase or the secretory phase of pulsatile insulin secretion. Metabolic signaling components are assigned regulatory, effectory, and/or homeostatic roles vis-à-vis their contribution to glucose sensing, signal transmission, and resetting the system. Taken together, these functions provide a framework for understanding how allostery, anaplerosis, and oxidative metabolism are integrated into the oscillatory behavior of the secretory pathway. By incorporating these temporal as well as newly discovered spatial aspects of β cell metabolism, we propose a much-refined MitoCat-MitoOx model of the signaling process for the field to evaluate. In this review, Merrins et al. discuss recent developments in our understanding of nutrient-stimulated insulin secretion, with a focus on oscillatory metabolic signaling. By integrating the temporal as well as newly identified spatial aspects of β cell metabolism, the authors propose a revised model of pulsatile insulin secretion.