A patient with glucose-6-phosphatase deficiency (von Gierke disease) presents with severe fasting hypoglycemia. Why does fasting hypoglycemia occur but postprandial hyperglycemia does not?

• A Fasting: glycogenolysis generates glucose-6-phosphate (G6P) that cannot be dephosphorylated to free glucose. Postprandial: dietary glucose enters directly as free glucose without needing dephosphorylation ✓
• B Fasting: gluconeogenesis is blocked because G6P cannot be hydrolysed. Postprandial: glucose-6-phosphate is shunted entirely to glycogen synthesis, preventing hyperglycemia
• C Fasting: G6P accumulation inhibits phosphoglucomutase, blocking both glycogenolysis and gluconeogenesis. Postprandial: intestinal sucrase provides free glucose bypassing the hepatic block
• D Fasting: insulin suppression fails due to G6P accumulation activating pancreatic beta cells. Postprandial: glucose enters directly via GLUT2 in the portal circulation

Explanation

Glucose-6-phosphatase (in the ER membrane) is required to release free glucose from hepatic glucose-6-phosphate derived from both glycogenolysis and gluconeogenesis. In G6Pase deficiency, G6P cannot be hydrolysed to free glucose during fasting, so blood glucose falls. After meals, dietary carbohydrates are absorbed and enter portal blood as free glucose (not requiring hepatic G6Pase), so postprandial glucose is normal or elevated. G6P accumulates and is shunted to glycogen (causing hepatomegaly) and via glycolysis to lactate (causing lactic acidosis).

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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