During a prolonged fast of 48 hours, plasma insulin is 3 µU/mL (low) and glucagon is 180 pg/mL (elevated). Which metabolic shift in the liver is most directly driven by this hormonal milieu?

• A Activation of glycogen phosphorylase and phosphoenolpyruvate carboxykinase (PEPCK) promoting glycogenolysis and gluconeogenesis
• B Activation of fatty acid synthase to generate adipose triglycerides for energy storage
• C Suppression of malonyl-CoA allowing fatty acid oxidation, with ketone body production serving as brain fuel
• D Both A and C are simultaneously and directly driven by glucagon-mediated cAMP signaling ✓

Explanation

Glucagon binds hepatic glucagon receptors, raising intracellular cAMP. This simultaneously activates PKA, which phosphorylates and activates glycogen phosphorylase (glycogenolysis) and upregulates PEPCK and other gluconeogenic enzymes. PKA-mediated phosphorylation of acetyl-CoA carboxylase also inhibits malonyl-CoA production, relieving CPT-1 inhibition and permitting massive fatty acid entry into mitochondria for β-oxidation and ketogenesis. After 48 h of fasting, hepatic glycogen is depleted and gluconeogenesis plus ketogenesis become the dominant glucose-sparing strategies.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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