Aberrant glucose metabolism underlies impaired macrophage differentiation in glycogen storage disease type Ib

Abstract Glycogen storage disease type Ib (GSD‐Ib) is an autosomal recessive disorder caused by a deficiency in the glucose‐6‐phosphate (G6P) transporter (G6PT) that is responsible for transporting G6P into the endoplasmic reticulum. GSD‐Ib is characterized by disturbances in glucose homeostasis, neutropenia, and neutrophil dysfunction. Although some studies have explored neutrophils abnormalities in GSD‐Ib, investigations regarding monocytes/macrophages remain limited so far. In this study, we examined the impact of G6PT deficiency on monocyte‐to‐macrophage differentiation using bone marrow‐derived monocytes from G6pt −/− mice as well as G6PT‐deficient human THP‐1 monocytes. Our findings revealed that G6PT‐deficient monocytes exhibited immature differentiation into macrophages. Notably, the impaired differentiation observed in G6PT‐deficient monocytes seemed to be associated with abnormal glucose metabolism, characterized by enhanced glucose consumption through glycolysis, even under quiescent conditions with oxidative phosphorylation. Furthermore, we observed a reduced secretion of inflammatory cytokines in G6PT‐deficient THP‐1 monocytes during the inflammatory response, despite their elevated glucose consumption. In conclusion, this study sheds light on the significance of G6PT in monocyte‐to‐macrophage differentiation and underscores its importance in maintaining glucose homeostasis and supporting immune response in GSD‐Ib. These findings may contribute to a better understanding of the pathogenesis of GSD‐Ib and potentially pave the way for the development of targeted therapeutic interventions.