Merrins Matthew J, Poudel Chetan, McKenna Joseph P, Ha Joon, Sherman Arthur, Bertram Richard, Satin Leslie S
Division of Endocrinology, Diabetes & Metabolism, Department of Medicine and Department of Biomolecular Chemistry, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
Department of Mathematics and Programs in Neuroscience and Molecular Biophysics, Florida State University, Tallahassee, Florida.
Biophys J. 2016 Feb 2;110(3):691-699. doi: 10.1016/j.bpj.2015.12.029.
Metabolism in islet β-cells displays oscillations that can trigger pulses of electrical activity and insulin secretion. There has been a decades-long debate among islet biologists about whether metabolic oscillations are intrinsic or occur in response to oscillations in intracellular Ca(2+) that result from bursting electrical activity. In this article, the dynamics of oscillatory metabolism were investigated using five different optical reporters. Reporter activity was measured simultaneously with membrane potential bursting to determine the phase relationships between the metabolic oscillations and electrical activity. Our experimental findings suggest that Ca(2+) entry into β-cells stimulates the rate of mitochondrial metabolism, accounting for the depletion of glycolytic intermediates during each oscillatory burst. We also performed Ca(2+) clamp tests in which we clamped membrane potential with the KATP channel-opener diazoxide and KCl to fix Ca(2+) at an elevated level. These tests confirm that metabolic oscillations do not require Ca(2+) oscillations, but show that Ca(2+) plays a larger role in shaping metabolic oscillations than previously suspected. A dynamical picture of the mechanisms of oscillations emerged that requires the restructuring of contemporary mathematical β-cell models, including our own dual oscillator model. In the companion article, we modified our model to account for these new data.
胰岛β细胞中的代谢呈现出振荡，这种振荡可触发电活动脉冲和胰岛素分泌。胰岛生物学家们围绕代谢振荡是内在的，还是由爆发性电活动导致的细胞内Ca(2+)振荡所引发，展开了长达数十年的争论。在本文中，我们使用五种不同的光学报告基因研究了振荡代谢的动力学。报告基因活性与膜电位爆发同时进行测量，以确定代谢振荡与电活动之间的相位关系。我们的实验结果表明，Ca(2+)进入β细胞会刺激线粒体代谢速率，这解释了每次振荡爆发期间糖酵解中间产物的消耗。我们还进行了Ca(2+)钳制试验，在试验中我们使用KATP通道开放剂二氮嗪和KCl钳制膜电位，将Ca(2+)固定在升高的水平。这些试验证实，代谢振荡并不需要Ca(2+)振荡，但表明Ca(2+)在塑造代谢振荡方面所起的作用比之前认为的更大。由此出现了一幅振荡机制的动态图景，这需要对当代数学β细胞模型进行重构，包括我们自己的双振荡器模型。在配套文章中，我们对模型进行了修改以纳入这些新数据。
