Mutations in SLC37A4, which encodes the intracellular glucose transporter G6PT, cause the rare glycogen storage disease type 1b (GSD1b). A long-term consequence of GSD1b is kidney failure, which requires KRT. The main protein markers of proximal tubule function, including NaPi2A, NHE3, SGLT2, GLUT2, and AQP1, are downregulated as part of the disease phenotype.

We utilized an inducible mouse model of GSD1b, TM-G6PT^–/–, to show that glycogen accumulation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry into proximal tubule cells and thus to prevent glycogen accumulation, we administered an SGLT2-inhibitor, dapagliflozin, to TM-G6PT^–/– mice.

In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase-I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis toward lysis and by restoring expression levels of the main proximal tubule functional markers.

We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat patients with GSD1b.

编码细胞内葡萄糖转运蛋白 G6PT 的SLC37A4突变会导致罕见的 1b 型糖原贮积病 (GSD1b)。GSD1b 的长期后果是肾衰竭，这需要 KRT。近曲小管功能的主要蛋白质标志物，包括 NaPi2A、NHE3、SGLT2、GLUT2 和 AQP1，作为疾病表型的一部分被下调。

我们利用 GS​​D1b 的诱导型小鼠模型 TM-G6PT ^–/–来证明糖原积累在改变近端小管形态和功能中起着至关重要的作用。^{为了限制葡萄糖进入近端小管细胞，从而防止糖原积累，我们给 TM-G6PT –/–}小鼠施用 SGLT2 抑制剂达格列净。

在近曲小管细胞中，G6PT 抑制会刺激己糖激酶-I 的上调和活性，从而增加细胞内代谢重吸收葡萄糖的可用性。达格列净通过促进从糖原合成到裂解的代谢转变以及恢复主要近端小管功能标记物的表达水平来防止糖原积累并改善肾脏形态。

我们为达格列净在保护 GSD1b 小鼠肾功能方面的功效提供了概念证明。我们的研究结果可以为重新利用该药物治疗 GSD1b 患者奠定基础。