Amino acids and lactic acid are used to synthesize new G6P in liver cells by the process of gluconeogenesis. The last step of normal gluconeogenesis, like the last step of glycogenolysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and PO4. Thus glucose-6-phosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting. The effect is amplified because the resulting high levels of glucose-6-phosphate inhibit earlier key steps in both glycogenolysis and gluconeogenesis. Pathophysiology
The principal metabolic effects of deficiency of glucose-6-phosphatase are hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia. The hypoglycemia of GSD I is termed "fasting", or "post-absorptive", usually about 4 hours after the complete digestion of a meal. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both glycogenolysis and gluconeogenesis. Fasting hypoglycemia is often the most significant problem in GSD I, and typically the problem that leads to the diagnosis. Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low insulin levels and high levels of glucagon and cortisol. Lactic acidosis arises from impairment of gluconeogenesis. Lactic acid is generated both in the liver and muscle and is oxidized by NAD+ to pyruvic acid and then converted via the gluconeogenic pathway to G6P. Accumulation of G6P inhibits conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with GSD I, it may not fall entirely to normal even when normal glucose levels are restored.
People with one copy of the faulty gene are carriers of the disease and have no symptoms. As with other autosomal recessive diseases, each child born to two carriers of the disease has a 25% chance of inheriting both copies of the faulty gene and manifesting the disease. Unaffected parents of a child with GSD I can be assumed to be carriers. Prenatal diagnosis has been made by fetal liver biopsy at 18–22 weeks of gestation, but no fetal treatment has been proposed. Prenatal diagnosis is possible with fetal DNA obtained by chorionic villus sampling when a fetus is known to be at risk.The most common forms of GSD I are designated GSD Ia and GSD Ib, the former accounting for over 80% of diagnosed cases and the latter for less than 20%. A few rarer forms have been described. GSD Ia results from mutations of G6PC, the gene for glucose-6-phosphatase, located on chromosome 17q21. GSD Ib results from mutations of the gene for SLC37A4 or "G6PT1", the glucose-6-phosphate transporter. GSD Ic results from mutations of SLC17A3 or SLC37A4.Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit is associated with a calcium binding protein, and three transport proteins (T1, T2, T3) that facilitate movement of glucose-6-phosphate (G6P), phosphate, and glucose (respectively) into and out of the enzyme.