Hepatic glucose sensing and gluconeogenesis are regulated by glucose-6-phosphatase (G6Pase). Glycogen storage disease type Ia (von Gierke disease) presents with severe fasting hypoglycemia because:
- A Deficient G6Pase prevents conversion of glucose-6-phosphate to free glucose; G6P accumulates and cannot exit the hepatocyte, blocking both glycogenolysis and gluconeogenesis contributions to blood glucose ✓
- B Deficient glucokinase prevents glucose phosphorylation, blocking glycogen synthesis and causing postprandial hyperglycemia instead of fasting hypoglycemia
- C Deficient glucose transporter GLUT2 prevents hepatic glucose uptake and release, causing fasting hypoglycemia and postprandial hyperglycemia
- D Deficient branching enzyme causes very long glycogen chains that cannot be mobilized by phosphorylase during fasting
Explanation
Glucose-6-phosphatase (G6Pase) is the final enzyme in both hepatic glycogenolysis and gluconeogenesis, converting G6P to free glucose for export. In GSD Ia, absent G6Pase means G6P accumulates; it cannot be dephosphorylated and remains trapped as G6P. Glycogen can be broken down by phosphorylase to G1P → G6P, and gluconeogenic substrates can generate G6P, but neither pathway can contribute to blood glucose because the terminal step is missing. This causes severe fasting hypoglycemia, hepatomegaly (glycogen accumulation), lactic acidosis (G6P shunted to glycolysis), hyperlipidemia, and hyperuricemia.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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Written and medically reviewed by the StethoPrep medical team.