Which hormone is primarily responsible for promoting hepatic gluconeogenesis during fasting?

• A. Cortisol
• B. Insulin
• C. Epinephrine
• D. Glucagon

Answer: (D)

Glucagon is the main signal that tells the liver to make glucose during fasting. When blood glucose falls, pancreatic alpha cells secrete glucagon, which binds to receptors on hepatocytes and activates the cAMP-PKA pathway. This leads to increased production of gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, driving the conversion of non-carbohydrate substrates (like lactate, amino acids, and glycerol) into glucose. At the same time, insulin levels drop, removing inhibition of gluconeogenesis, which further promotes hepatic glucose production. Epinephrine also promotes glucose release but is more about rapid, short-term mobilization in stress or exercise, not the primary driver during fasting. Cortisol supports gluconeogenesis over a longer term by increasing enzyme expression, but the immediate, principal signal during fasting is glucagon.