Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Cell Metab. 2022 Jul 5;34(7):947-968. doi: 10.1016/j.cmet.2022.06.003. Epub 2022 Jun 20.
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 K 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 Mito-Mito model of the signaling process for the field to evaluate.
在这篇综述中，我们重点介绍了我们对营养诱导胰岛素分泌的理解的最新进展，这些进展挑战了“经典”模型的一个关键方面，即在该模型中，氧化磷酸化驱动的 ATP 产生增加会关闭 K 通道。我们讨论了内在β细胞代谢振荡的重要性；相关代谢循环、穿梭和分流的阶段性对齐；以及它们的时间和区室关系如何与脉冲式胰岛素分泌的触发相或分泌相对齐。代谢信号成分根据其对葡萄糖感应、信号传递和系统重置的贡献，被赋予调节、效应或/和稳态作用。总的来说，这些功能为理解变构、氨甲酰磷酸和氧化代谢如何整合到分泌途径的振荡行为提供了一个框架。通过结合β细胞代谢的这些时间和新发现的空间方面，我们提出了一个经过改进的线粒体-线粒体信号转导模型，供该领域评估。
