Institute of Dynamics and Vibrations, Technische Universität Braunschweig, D-38106 Braunschweig, Germany.
Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, D-38106 Braunschweig, Germany.
Int J Mol Sci. 2023 Feb 6;24(4):3206. doi: 10.3390/ijms24043206.
The stimulus-secretion coupling of the pancreatic beta cell is particularly complex, as it integrates the availability of glucose and other nutrients with the neuronal and hormonal input to generate rates of insulin secretion that are appropriate for the entire organism. It is beyond dispute however, that the cytosolic Ca concentration plays a particularly prominent role in this process, as it not only triggers the fusion of insulin granules with the plasma membrane, but also regulates the metabolism of nutrient secretagogues and affects the function of ion channels and transporters. In order to obtain a better understanding of the interdependence of these processes and, ultimately, of the entire beta cell as a working system, models have been developed based on a set of nonlinear ordinary differential equations, and were tested and parametrized on a limited set of experiments. In the present investigation, we have used a recently published version of the beta cell model to test its ability to describe further measurements from our own experimentation and from the literature. The sensitivity of the parameters is quantified and discussed; furthermore, the possible influence of the measuring technique is taken into account. The model proved to be powerful in correctly describing the depolarization pattern in response to glucose and the reaction of the cytosolic Ca concentration to stepwise increases of the extracellular K concentration. Additionally, the membrane potential during a KATP channel block combined with a high extracellular K concentration could be reproduced. In some cases, however, a slight change of a single parameter led to an abrupt change in the cellular response, such as the generation of a Ca oscillation with high amplitude and high frequency. This raises the question as to whether the beta cell may be a partially unstable system or whether further developments in modeling are needed to achieve a generally valid description of the stimulus-secretion coupling of the beta cell.
胰岛β细胞的分泌耦联特别复杂，因为它整合了葡萄糖和其他营养物质的可用性以及神经元和激素的输入，以产生适合整个机体的胰岛素分泌率。然而，毫无疑问，细胞质 Ca 浓度在这个过程中起着特别突出的作用，因为它不仅触发胰岛素颗粒与质膜融合，而且还调节营养分泌刺激物的代谢，并影响离子通道和转运体的功能。为了更好地理解这些过程的相互依存关系，最终理解整个β细胞作为一个工作系统，已经基于一组非线性常微分方程开发了模型，并在有限的一组实验中进行了测试和参数化。在本研究中，我们使用了最近发表的β细胞模型版本来测试其描述我们自己的实验和文献中进一步测量的能力。量化并讨论了参数的敏感性；此外，还考虑了测量技术的可能影响。该模型在正确描述葡萄糖引起的去极化模式和细胞溶质 Ca 浓度对细胞外 K 浓度的逐步增加的反应方面表现出强大的功能。此外，还可以再现 KATP 通道阻断和高细胞外 K 浓度结合时的膜电位。然而，在某些情况下，单个参数的微小变化会导致细胞反应的突然变化，例如产生具有高幅度和高频的 Ca 振荡。这就提出了一个问题，即β细胞是否可能是一个部分不稳定的系统，或者是否需要进一步的建模发展来实现对β细胞的刺激-分泌耦联的普遍有效描述。
