Fazli Mehran, Vo Theodore, Bertram Richard
Florida State University, Department of Mathematics, Tallahassee, FL, United States.
Monash University, School of Mathematics, Clayton, Victoria, Australia.
J Theor Biol. 2020 Sep 21;501:110346. doi: 10.1016/j.jtbi.2020.110346. Epub 2020 Jun 4.
Insulin is secreted by pancreatic β-cellsthat are electrically coupled into micro-organs called islets of Langerhans. The secretion is due to the influx of Caions that accompany electrical impulses, which are clustered into bursts. So-called "medium bursting" occurs in many β-cellsin intact islets, while in other islets the β-cellsexhibit "slow bursting", with a much longer period. Each burst brings in Ca that, through exocytosis, results in insulin secretion. When isolated from an islet, β-cellsbehave very differently. The electrical activity is much noisier, and consists primarily of trains of irregularly-timed spikes, or fast or slow bursting. Medium bursting, so often seen in intact islets, is rarely if ever observed. In this study, we examine what the isolated cell behavior can tell us about the mechanism for bursting in intact islets. A previous mathematical study concluded that the slow bursting observed in isolated β-cells, and therefore most likely in islets, must be due to intrinsic glycolytic oscillations, since this mechanism for bursting is robust to noise. It was demonstrated that an alternate mechanism, phantom bursting, was very sensitive to noise, and therefore could not account for the slow bursting in single cells. We re-examine these conclusions, motivated by recent experimental and mathematical modeling evidence that slow bursting in intact islets is, at least in many cases, driven by the phantom bursting mechanism and not endogenous glycolytic oscillations. We employ two phantom bursting models, one minimal and the other more biophysical, to determine the sensitivity of medium and slow bursting to electrical current noise. In the minimal model, both forms of bursting are highly sensitive to noise. In the biophysical model, while medium bursting is sensitive to noise, slow bursting is much less sensitive. This suggests that the slow bursting seen in isolated β-cellsmay be due to a phantom bursting mechanism, and by extension, slow bursting in intact islets may also be driven by this mechanism.
胰岛素由胰腺β细胞分泌,这些β细胞通过电耦合形成称为朗格汉斯岛的微器官。分泌是由于伴随着电脉冲的钙离子流入,这些电脉冲聚集成簇。在完整胰岛的许多β细胞中会出现所谓的“中等爆发”,而在其他胰岛中,β细胞表现出“缓慢爆发”,周期要长得多。每次爆发都会引入钙离子,通过胞吐作用导致胰岛素分泌。当从胰岛中分离出来时,β细胞的行为会大不相同。电活动的噪声要大得多,主要由一系列不规则时间的尖峰或快速或缓慢的爆发组成。在完整胰岛中经常看到的中等爆发,很少被观察到。在这项研究中,我们研究了分离细胞的行为能告诉我们关于完整胰岛爆发机制的哪些信息。之前的一项数学研究得出结论,在分离的β细胞中观察到的缓慢爆发,因此很可能在胰岛中也是如此,一定是由于内在糖酵解振荡,因为这种爆发机制对噪声具有鲁棒性。结果表明,另一种机制——幻影爆发,对噪声非常敏感,因此无法解释单个细胞中的缓慢爆发。我们重新审视这些结论,这是受到最近的实验和数学建模证据的推动,即完整胰岛中的缓慢爆发,至少在许多情况下,是由幻影爆发机制驱动的,而不是内源性糖酵解振荡。我们采用了两个幻影爆发模型,一个是最小模型,另一个更具生物物理性质,以确定中等爆发和缓慢爆发对电流噪声的敏感性。在最小模型中,两种形式的爆发对噪声都高度敏感。在生物物理模型中,虽然中等爆发对噪声敏感,但缓慢爆发对噪声的敏感性要小得多。这表明在分离的β细胞中看到的缓慢爆发可能是由于幻影爆发机制,由此推断,完整胰岛中的缓慢爆发也可能由该机制驱动。