Metabolic cycles and signals for insulin secretion

In this perspective 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 K(ATP) 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 signalling 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 Mito(Cat)-Mito(Ox) model of the signaling process for the field to evaluate.