Neutropenia in type Ib glycogen storage disease

Abstract

Purpose of review Glycogen storage disease type Ib, characterized by disturbed glucose homeostasis, neutropenia, and neutrophil dysfunction, is caused by a deficiency in a ubiquitously expressed glucose-6-phosphate transporter (G6PT). G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the endoplasmic reticulum, in which it is hydrolyzed to glucose either by a liver/kidney/intestine-restricted glucose-6-phosphatase-α (G6Pase-α) or by a ubiquitously expressed G6Pase-β. The role of the G6PT/G6Pase-α complex is well established and readily explains why G6PT disruptions disturb interprandial blood glucose homeostasis. However, the basis for neutropenia and neutrophil dysfunction in glycogen storage disease type Ib is poorly understood. Recent studies that are now starting to unveil the mechanisms are presented in this review. Recent findings Characterization of G6Pase-β and generation of mice lacking either G6PT or G6Pase-β have shown that neutrophils express the G6PT/G6Pase-β complex capable of producing endogenous glucose. Loss of G6PT activity leads to enhanced endoplasmic reticulum stress, oxidative stress, and apoptosis that underlie neutropenia and neutrophil dysfunction in glycogen storage disease type Ib. Summary Neutrophil function is intimately linked to the regulation of glucose and G6P metabolism by the G6PT/G6Pase-β complex. Understanding the molecular mechanisms that govern energy homeostasis in neutrophils has revealed a previously unrecognized pathway of intracellular G6P metabolism in neutrophils.