pancreas glucose model

The pancreas plays a critical role in maintaining glucose homeostasis through the secretion of hormones from the islets of Langerhans. Glucose-stimulated insulin secretion (GSIS) by the pancreatic beta-cell is the main mechanism for reducing elevated plasma glucose.
Here we present a systematic modeling workflow for the development of kinetic pathway models using the Systems Biology Markup Language (SBML). An important factor was the reproducibility and exchangeability of the model, which allowed the use of various existing tools.
The workflow was applied to construct a novel data-driven kinetic model of GSIS in the pancreatic beta-cell based on experimental and clinical data from 39 studies spanning 50 years of pancreatic, islet, and beta-cell research in humans, rats, mice, and cell lines. The model consists of detailed glycolysis and phenomenological equations for insulin secretion coupled to cellular energy state, ATP dynamics and (ATP/ADP ratio).
Key findings of our work are that in GSIS there is a glucose-dependent increase in almost all intermediates of glycolysis. This increase in glycolytic metabolites is accompanied by an increase in energy metabolites, especially ATP and NADH. One of the few decreasing metabolites is ADP, which, in combination with the increase in ATP, results in a large increase in ATP/ADP ratios in the beta-cell with increasing glucose. Insulin secretion is dependent on ATP/ADP, resulting in glucose-stimulated insulin secretion.

胰腺通过胰岛（islets of Langerhans）分泌激素，在维持葡萄糖稳态（glucose homeostasis）中发挥关键作用。胰腺β细胞的葡萄糖刺激胰岛素分泌（Glucose-stimulated insulin secretion, GSIS）是降低升高的血浆葡萄糖水平的主要机制。
本研究提出一套系统化建模流程，用于基于系统生物学标记语言（Systems Biology Markup Language, SBML）构建动力学通路模型。该流程的核心考量因素之一是保障模型的可复现性与可交换性，使其可兼容各类现有工具。
我们将该流程应用于构建全新的数据驱动型胰腺β细胞GSIS动力学模型，该数据集整合了50年来针对人类、大鼠、小鼠及细胞系开展的胰腺、胰岛与β细胞研究的39项实验与临床数据。该模型包含详尽的糖酵解通路，以及与细胞能量状态、ATP动力学及ATP/ADP比值耦合的胰岛素分泌现象学方程。
本研究的关键发现包括：在GSIS过程中，几乎所有糖酵解中间产物均随葡萄糖浓度升高而增加。这类糖酵解代谢物的上调伴随能量代谢物（尤其是ATP与NADH）的水平升高。少数出现水平下降的代谢物之一为ADP，其与ATP的升高共同导致β细胞内ATP/ADP比值随葡萄糖浓度提升而显著升高。胰岛素分泌依赖于ATP/ADP比值，进而实现葡萄糖刺激的胰岛素分泌。