The glucose-6-phosphatase system in human development

Abstract

The classical role of glucose-6-phosphatase in liver and kidney is the production of glucose for release into blood. In liver, glucose-6-phosphatase catalyses the terminal step of glycogenolysis and gluconeogenesis. Abnormally low hepatic glucose-6-phosphatase activity is found in human genetic deficiencies i.e. glycogen storage disease type I and in cases of developmental delay, found predominantly in preterm infants. In contrast, abnormally high liver glucose-6-phosphatase occurs in poorly controlled or untreated diabetes mellitus. Hepatic glucose-6-phosphatase is an integral endoplasmic reticulum (and nuclear membrane) protein and it is part of a multicomponent system. Its active site is situated inside the lumen of the endoplasmic reticulum and transport proteins are needed to allow its substrates glucose-6-phosphate (and pyrophosphate) and its products phosphate and glucose to cross the endoplasmic reticulum membrane. In addition, a calcium binding protein is also associated with the glucose-6-phosphatase enzyme. Immunohistochemical studies, in combination with image analysis, have shown that glucose-6-phosphatase is present in liver and kidney and also in specific cell types in a variety of human tissues, for example Leydig cells in the testis and some astrocytes in the brain. Where practicable, enzymatic analysis, direct transport assays and/or immunological detection of the endoplasmic reticulum glucose and phosphate transport proteins have been used to demonstrate the presence and activity of the whole glucose-6-phosphatase system. The distribution of the human glucose-6-phosphatase system changes dramatically during development with a different spatial and temporal pattern in each tissue. The most unexpected localization was in circulating, predominantly nucleated, embryonic and early fetal red blood cells.