Department of Mathematics and Programs in Neuroscience and Molecular Biophysics, Florida State University, Tallahassee, FL
Department of Pharmacology and Brehm Center for Diabetes Research, University of Michigan Medical School, Ann Arbor, MI.
Diabetes. 2018 Mar;67(3):351-359. doi: 10.2337/dbi17-0004.
Insulin secretion from pancreatic islet β-cells occurs in a pulsatile fashion, with a typical period of ∼5 min. The basis of this pulsatility in mouse islets has been investigated for more than four decades, and the various theories have been described as either qualitative or mathematical models. In many cases the models differ in their mechanisms for rhythmogenesis, as well as other less important details. In this Perspective, we describe two main classes of models: those in which oscillations in the intracellular Ca concentration drive oscillations in metabolism, and those in which intrinsic metabolic oscillations drive oscillations in Ca concentration and electrical activity. We then discuss nine canonical experimental findings that provide key insights into the mechanism of islet oscillations and list the models that can account for each finding. Finally, we describe a new model that integrates features from multiple earlier models and is thus called the Integrated Oscillator Model. In this model, intracellular Ca acts on the glycolytic pathway in the generation of oscillations, and it is thus a hybrid of the two main classes of models. It alone among models proposed to date can explain all nine key experimental findings, and it serves as a good starting point for future studies of pulsatile insulin secretion from human islets.
胰岛β细胞的胰岛素分泌呈脉冲式，典型的周期约为 5 分钟。在过去的四十多年里，人们一直在研究这种脉冲式分泌在小鼠胰岛中的基础，并且已经描述了各种定性或数学模型。在许多情况下，这些模型在节奏发生的机制以及其他不太重要的细节上存在差异。在本观点中，我们描述了两种主要的模型：一种是细胞内 Ca 浓度的振荡驱动代谢的振荡，另一种是内在代谢的振荡驱动 Ca 浓度和电活动的振荡。然后，我们讨论了九个典型的实验发现，这些发现为胰岛振荡的机制提供了关键的见解，并列出了可以解释每个发现的模型。最后，我们描述了一个新的模型，该模型整合了多个早期模型的特征，因此被称为综合振荡器模型。在这个模型中，细胞内 Ca 作用于糖酵解途径以产生振荡，因此它是两种主要模型的混合体。它是迄今为止提出的所有模型中唯一能够解释所有九个关键实验发现的模型，并且它是未来研究人类胰岛脉冲式胰岛素分泌的良好起点。
