Stolarczyk Emilie, Le Gall Maude, Even Patrick, Houllier Anne, Serradas Patricia, Brot-Laroche Edith, Leturque Armelle
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris6, UMR S 872, Paris, France.
PLoS One. 2007 Dec 12;2(12):e1288. doi: 10.1371/journal.pone.0001288.
Mammals must sense the amount of sugar available to them and respond appropriately. For many years attention has focused on intracellular glucose sensing derived from glucose metabolism. Here, we studied the detection of extracellular glucose concentrations in vivo by invalidating the transduction pathway downstream from the transporter-detector GLUT2 and measured the physiological impact of this pathway.
METHODOLOGY/PRINCIPAL FINDINGS: We produced mice that ubiquitously express the largest cytoplasmic loop of GLUT2, blocking glucose-mediated gene expression in vitro without affecting glucose metabolism. Impairment of GLUT2-mediated sugar detection transiently protected transgenic mice against starvation and streptozotocin-induced diabetes, suggesting that both low- and high-glucose concentrations were not detected. Transgenic mice favored lipid oxidation, and oral glucose was slowly cleared from blood due to low insulin production, despite massive urinary glucose excretion. Kidney adaptation was characterized by a lower rate of glucose reabsorption, whereas pancreatic adaptation was associated with a larger number of small islets.
CONCLUSIONS/SIGNIFICANCE: Molecular invalidation of sugar sensing in GLUT2-loop transgenic mice changed multiple aspects of glucose homeostasis, highlighting by a top-down approach, the role of membrane glucose receptors as potential therapeutic targets.
哺乳动物必须感知自身可利用的糖量并做出适当反应。多年来，注意力一直集中在源自葡萄糖代谢的细胞内葡萄糖感知上。在此，我们通过使转运体 - 检测蛋白GLUT2下游的转导途径失效，研究了体内细胞外葡萄糖浓度的检测，并测量了该途径的生理影响。
方法/主要发现：我们培育出了在全身普遍表达GLUT2最大细胞质环的小鼠，这在体外阻断了葡萄糖介导的基因表达，同时不影响葡萄糖代谢。GLUT2介导的糖检测受损使转基因小鼠暂时免受饥饿和链脲佐菌素诱导的糖尿病影响，这表明低葡萄糖浓度和高葡萄糖浓度均未被检测到。转基因小鼠倾向于脂质氧化，尽管有大量尿糖排泄，但由于胰岛素分泌减少，口服葡萄糖从血液中清除缓慢。肾脏适应性表现为葡萄糖重吸收率降低，而胰腺适应性与大量小胰岛有关。
结论/意义：GLUT2环转基因小鼠中糖感知的分子失效改变了葡萄糖稳态的多个方面，通过自上而下的方法突出了膜葡萄糖受体作为潜在治疗靶点的作用。
