Tagliavini Alessia, Pedersen Morten Gram
Department of Information Engineering, University of Padova, Padova, Italy.
Department of Information Engineering, University of Padova, Padova, Italy.
Biophys J. 2017 Jan 10;112(1):162-171. doi: 10.1016/j.bpj.2016.11.3199.
Glucagon-like peptide 1 (GLP-1) is secreted by intestinal L-cells, and augments glucose-induced insulin secretion, thus playing an important role in glucose control. The stimulus-secretion pathway in L-cells is still incompletely understood and a topic of debate. It is known that GLP-1 secreting cells can sense glucose to promote electrical activity either by the electrogenic sodium-glucose cotransporter SGLT1, or by closure of ATP-sensitive potassium channels after glucose metabolism. Glucose also has an effect on GLP-1 secretion downstream of electrical activity. An important aspect to take into account is the spatial organization of the cell. Indeed, the glucose transporter GLUT2 is located at the basolateral, vascular side, while SGLT1 is exposed to luminal glucose at the apical side of the cell, suggesting that the two types of transporters play different roles in glucose sensing. Here, we extend our recent model of electrical activity in primary L-cells to include spatiotemporal glucose and Ca dynamics, and GLP-1 secretion. The model confirmed that glucose transportation into the cell through SGLT1 cotransporters can induce Ca influx and release of GLP-1 as a result of electrical activity, while glucose metabolism alone is insufficient to depolarize the cell and evoke GLP-1 secretion in the model, suggesting a crucial role for SGLT1 in triggering GLP-1 release in agreement with experimental studies. We suggest a secondary, but participating, role of GLUT2 and glucose metabolism for GLP-1 secretion via an amplifying pathway that increases the secretion rate at a given Ca level.
胰高血糖素样肽1（GLP-1）由肠道L细胞分泌，可增强葡萄糖诱导的胰岛素分泌，因此在血糖控制中发挥重要作用。L细胞中的刺激-分泌途径仍未完全了解，是一个有争议的话题。已知分泌GLP-1的细胞可通过电中性钠-葡萄糖共转运蛋白SGLT1感知葡萄糖以促进电活动，或在葡萄糖代谢后通过关闭ATP敏感性钾通道来实现。葡萄糖在电活动下游也对GLP-1分泌有影响。需要考虑的一个重要方面是细胞的空间组织。实际上，葡萄糖转运蛋白GLUT2位于基底外侧、血管侧，而SGLT1在细胞顶端侧暴露于管腔葡萄糖，这表明这两种类型的转运蛋白在葡萄糖感知中发挥不同作用。在此，我们扩展了我们最近关于原代L细胞电活动的模型，以纳入时空葡萄糖和钙动态以及GLP-1分泌。该模型证实，葡萄糖通过SGLT1共转运蛋白进入细胞可由于电活动诱导钙内流并释放GLP-1，而仅葡萄糖代谢不足以使细胞去极化并在模型中引发GLP-1分泌，这表明SGLT1在触发GLP-1释放中起关键作用，这与实验研究一致。我们提出GLUT2和葡萄糖代谢通过一条放大途径对GLP-1分泌起次要但参与的作用，该途径在给定钙水平下增加分泌速率。
