During a prolonged fast of 48 hours, the liver relies heavily on gluconeogenesis. Which regulatory mechanism specifically prevents simultaneous futile cycling between pyruvate kinase and phosphoenolpyruvate carboxykinase (PEPCK) during this state?

• A Allosteric activation of pyruvate kinase by fructose-2,6-bisphosphate
• B Glucagon-driven cAMP-PKA phosphorylation inactivates liver pyruvate kinase while inducing PEPCK transcription ✓
• C Insulin activates pyruvate kinase via dephosphorylation while suppressing PEPCK
• D Acetyl-CoA allosterically inhibits PEPCK while activating pyruvate kinase

Explanation

Glucagon elevates hepatic cAMP, activating PKA, which phosphorylates and inactivates liver pyruvate kinase — thereby preventing pyruvate formation from PEP. Simultaneously, glucagon/cAMP signaling induces PEPCK gene transcription (via CREB and PGC-1alpha), driving gluconeogenic flux from oxaloacetate to PEP. This reciprocal hormonal control prevents futile cycling. Fructose-2,6-bisphosphate is actually lowered by glucagon signaling, which simultaneously inhibits PFK-1 (glycolysis) and activates fructose-1,6-bisphosphatase (gluconeogenesis).

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

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