Dapagliflozin Prevents Kidney Glycogen Accumulation and Improves Renal Proximal Tubule Cell Functions in a Mouse Model of Glycogen Storage Disease Type 1b

Background Mutations inSLC37A4, which encodes the intracellular glucose transporter G6PT, cause therare 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. Methods We utilized an inducible mouse model of GSD1b, TM-G6PT(-/-), to show that glycogen accumu-lation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry intoproximal tubule cells and thus to prevent glycogen accumulation, we administered an SGLT2-inhibitor,dapagliflozin, to TM-G6PT(-/-)mice. Results 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 preventedglycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogensynthesis toward lysis and by restoring expression levels of the main proximal tubule functional markers. Conclusion We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function inGSD1b mice. Ourfindings could represent the basis for repurposing this drug to treat patients with GSD1b

Automated summary

This study demonstrates the efficacy of dapagliflozin in preserving kidney function in GSD1b mice, which could provide a new therapeutic option for patients with GSD1b.