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-alpha (G6Pase-alpha) or by a ubiquitously expressed G6Pase-beta. The role of the G6PT/G6Pase-alpha 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-beta and generation of mice lacking either G6PT or G6Pase-beta have shown that neutrophils express the G6PT/G6Pase-beta 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-beta complex. Understanding the molecular mechanisms that govern energy homeostasis in neutrophils has revealed a previously unrecognized pathway of intracellular G6P metabolism in neutrophils.

Figure 1

Proposed pathways for G6P metabolism in wild-type, G6pt^−/− and G6pc3^−/− neutrophils. Glucose transported into the cytoplasm via GLUT1 is metabolized by hexokinase to G6P which can participate in glycolysis, hexose monophosphate shunt (HMS), glycogen synthesis, or be translocated into the lumen of the ER by the G6PT. In wild-type neutrophils, G6P localized within the ER lumen can be hydrolyzed by G6Pase-β and the resulting glucose transported back into the cytoplasm to reenter any of the previously mentioned cytoplasmic pathways. In G6pt^−/− neutrophils which lack a functional G6PT, cytoplasmic G6P can not be translocated into the lumen of the ER and in G6pc3^−/− neutrophils, which lack a functional G6Pase-β, ER-localized G6P can not be recycled to the cytoplasm. The GLUT1 transporter, responsible for the transport of glucose in and out of the cell, is shown embedded in the plasma membrane. The G6PT transporter, responsible for the transport of G6P into the ER and G6Pase-β, responsible for hydrolyzing G6P to glucose and phosphate, are shown embedded in the ER membrane by 10 and 9 transmembrane helices, respectively.