Novel murine model provides insights into early-onset of kidney disease in glycogen storage disease type Ib.

Glycogen storage disease type Ib (GSD-Ib), caused by a deficiency of the glucose-6-phosphate transporter (G6PT), is characterized by impaired glucose homeostasis and progressive renal dysfunction. Using G6pt-deficient (G6pt-/-) mice, which closely recapitulate the pathophysiology of GSD-Ib, we previously demonstrated that GSD-Ib nephropathy is marked by disrupted renal homeostasis, acute kidney injury, and fibrosis. However, due to the severity of the metabolic defect, G6pt-/- mice typically fail to survive beyond three weeks of age, limiting the study of disease progression in adulthood. To overcome this limitation, we generated liver human G6PT-augmented, kidney G6PT-deficient (L-hG6PT/K-/-) mice, which restore hepatic G6PT expression to support survival while maintaining G6PT deficiency in the kidney. We show that adult L-hG6PT/K-/- mice develop renal abnormalities similar to those seen in 3-week-old global G6pt-/- mice. Importantly, unlike the younger cohort, 12-week-old L-hG6PT/K-/- mice exhibit a progressive decline in renal function accompanied by marked fibrosis. These findings establish L-hG6PT/K-/- mice as a robust and physiologically relevant model for investigating the mechanisms and progression of GSD-Ib nephropathy in mature animals.