page_title: Glucose 6-phosphatase
section_title: Clinical significance
hierarchical_section_title: Glucose 6-phosphatase / Clinical significance
caption_attribution_description: English: This is a hierarchical chart showing the various components that constitute Glucose-6-phosphatase system deficiency. Specifically it shows the effects of Glucose-6-phosphatase subunit-alpha, Glucose-6-transporters, and Glucose-6-phosphatase subunit-beta.
context_page_description: Glucose 6-phosphatase is an enzyme that hydrolyzes glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose. Glucose is then exported from the cell via glucose transporter membrane proteins. This catalysis completes the final step in gluconeogenesis and therefore plays a key role in the homeostatic regulation of blood glucose levels.
  Glucose 6-phosphatase is a complex of multiple component proteins, including transporters for G6P, glucose, and phosphate. The main phosphatase function is performed by the glucose 6-phosphatase catalytic subunit. In humans, there are three isozymes of the catalytic subunit: glucose 6-phosphatase-α, encoded by G6PC; IGRP, encoded by G6PC2; and glucose 6-phosphatase-β, encoded by G6PC3.
  Glucose 6-phosphatase-α and glucose 6-phosphatase-β are both functional phosphohydrolases, and have similar active site structure, topology, mechanism of action, and kinetic properties with respect to G6P hydrolysis. In contrast, IGRP has almost no hydrolase activity, and may play a different role in stimulating pancreatic insulin secretion.
context_section_description: Mutations of the glucose 6-phosphatase system, to be specific the glucose 6-phosphatase-α subunit (glucose 6-phosphatase-α), glucose 6-transporter (G6PT), and glucose 6-phosphatase-β (glucose 6-phosphatase-β or G6PC3) subunits lead to deficiencies in the maintenance of interprandial glucose homeostasis and neutrophil function and homeostasis. Mutations in both glucose 6-phosphatase-α and G6PT lead to glycogen storage disease type I (GSD 1, von Gierke's disease). To be specific, mutations in the glucose-6-phosphatase-α lead to Glycogen Storage Disease Type-1a, which is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. GSD-1a constitutes approximately 80% of GSD-1 cases that present clinically. Absence of G6PT leads to GSD-1b (GSD-1b), which is characterized by the lack of a G6PT and represents 20% of the cases that present clinically. 
  The specific cause of the GSD-1a stems from nonsense mutations, insertions/deletions with or without a shift in the reading frame, or splice site mutations that occur at the genetic level. The missense mutations affect the two large luminal loops and transmembrane helices of glucose 6-phosphatase-α, abolishing or greatly reducing activity of the enzyme. The specific cause of GSD-1b stems from "severe" mutations such as splice site mutations, frame-shifting mutations, and substitutions of a highly conserved residue that completely destroyed G6PT activity. These mutations lead to the prevalence of GSD-1 by preventing the transport of glucose-6-phosphate (G6P) into the luminal portion of the ER and also inhibiting the conversion of  G6P into glucose to be used by the cell.
  The third type of glucose 6-phosphatase deficiency, glucose 6-phosphatase-β deficiency, is characterized by a congenital neutropenia syndrome in which neutrophils exhibit enhanced endoplasmic reticulum (ER) stress, increased apoptosis, impaired energy homeostasis, and impaired functionality. It can also lead to cardiac and urogenital malformations. This third class of deficiency is also affected by a G6PT deficiency as glucose-6-phosphatase-β also lies within the ER lumen and thus can lead to similar symptoms of glucose-6-phosphatase-β deficiency be associated with GSD-1b. Furthermore, recent studies have elucidated this area of similarity between both deficiencies and have shown that aberrant glycosylation occurs in both deficiencies. The neutrophil glycosylation has a profound effect on neutrophil activity and thus may also be classified as a congenital glycosylation disorder as well.
  The major function of glucose 6-phosphatase-β has been determined to provide recycled glucose to the cytoplasm of neutrophils in order maintain normal function. Disruption of the glucose to G6P ratio due to significant decrease intracellular glucose levels cause significant disruption of glycolysis and HMS. Unless countered by uptake of extracellular glucose this deficiency leads to neutrophil dysfunction.
  Vanadium compounds such as vanadyl sulfate have been shown to inhibit the enzyme, and thus increase the insulin sensitivity in vivo in diabetics, as assessed by the hyperinsulinemic clamp technique, which may have potential therapeutic implications
caption: Breakdown of the various constituents of glucose 6-phosphatase system deficiency
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