Grubelnik Vladimir, Zmazek Jan, Markovič Rene, Gosak Marko, Marhl Marko
Faculty of Electrical Engineering and Computer Science, University of Maribor, Maribor SI-2000, Slovenia.
Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor SI-2000, Slovenia.
J Theor Biol. 2020 May 21;493:110213. doi: 10.1016/j.jtbi.2020.110213. Epub 2020 Feb 25.
We present a mathematical model of the energy-driven metabolic switch for glucagon and insulin secretion from pancreatic alpha and beta cells, respectively. The energy status related to hormone secretion is studied for various glucose concentrations. Additionally, the physiological response is studied with regards to the presence of other metabolites, particularly the free-fatty acids. At low glucose, the ATP production in alpha cells is high due to free-fatty acids oxidation in mitochondria, which enables glucagon secretion. When the glucose concentration is elevated above the threshold value, the glucagon secretion is switched off due to the contribution of glycolytic ATP production, representing an "anaerobic switch". On the other hand, during hypoglycemia, the ATP production in beta cells is low, reflecting a "waiting state" for glucose as the main metabolite. When glucose is elevated above the threshold value, the oxidative fate of glucose in mitochondria is the main source of energy required for effective insulin secretion, i.e. the "aerobic switch". Our results show the importance of well-regulated and fine-tuned energetic processes in pancreatic alpha and beta cells required for efficient hormone secretion and hence effective blood glucose regulation. These energetic processes have to be appropriately switched on and off based on the sensing of different metabolites by alpha and beta cells. Our computational results indicate that disturbances in cell energetics (e.g. mitochondrial dysfunction), and dysfunctional metabolite sensing and distribution throughout the cell might be related to pathologies such as metabolic syndrome and diabetes.
我们提出了一个能量驱动的代谢开关数学模型，分别用于胰腺α细胞和β细胞分泌胰高血糖素和胰岛素。针对不同的葡萄糖浓度，研究了与激素分泌相关的能量状态。此外，还研究了其他代谢物（特别是游离脂肪酸）存在时的生理反应。在低葡萄糖水平时，α细胞中的ATP生成量较高，这是由于线粒体中游离脂肪酸的氧化，从而使得胰高血糖素得以分泌。当葡萄糖浓度升高到阈值以上时，由于糖酵解产生的ATP的作用，胰高血糖素分泌被关闭，这代表了一种“无氧开关”。另一方面，在低血糖期间，β细胞中的ATP生成量较低，这反映了作为主要代谢物的葡萄糖的“等待状态”。当葡萄糖升高到阈值以上时，线粒体中葡萄糖的氧化代谢是有效胰岛素分泌所需能量的主要来源，即“有氧开关”。我们的结果表明，胰腺α细胞和β细胞中调节良好且微调的能量过程对于高效激素分泌以及有效的血糖调节至关重要。这些能量过程必须根据α细胞和β细胞对不同代谢物的感知而适当地开启和关闭。我们的计算结果表明，细胞能量学的紊乱（例如线粒体功能障碍）以及代谢物在整个细胞中的功能失调的感知和分布可能与诸如代谢综合征和糖尿病等病理状况有关。
