Which of the following is the primary mechanism by which glucagon raises blood glucose in the fasting state?

Explanation

## Glucagon's Mechanism of Glucose Homeostasis ### Glucagon Receptor Signaling **Key Point:** Glucagon binds to **G-protein coupled receptors (GPCR)** on hepatocyte cell membranes, activating the **adenylyl cyclase → cAMP → protein kinase A (PKA)** cascade. This is the primary mechanism for raising blood glucose. ### Hepatic Effects of Glucagon Glucagon stimulates two major pathways in the liver: | Pathway | Enzyme Activated | Effect | Outcome | |---------|-----------------|--------|----------| | **Glycogenolysis** | Phosphorylase kinase → Glycogen phosphorylase | Glycogen → Glucose-1-P → Glucose | Rapid glucose release (minutes) | | **Gluconeogenesis** | PEPCK, FBPase-1 | Lactate, amino acids, glycerol → Glucose | Sustained glucose production (hours) | ### Mechanism of PKA Activation 1. Glucagon binds GPCR → G~s~ protein activation 2. Adenylyl cyclase activated → ↑ cAMP 3. cAMP binds regulatory subunits of PKA → PKA activation 4. PKA phosphorylates: - **Phosphorylase kinase** → Glycogen phosphorylase activation → Glycogenolysis - **Acetyl-CoA carboxylase** → Inhibition → ↓ Fatty acid synthesis, ↑ Fatty acid oxidation - **CREB** (cAMP Response Element Binding protein) → ↑ Gene transcription of gluconeogenic enzymes **High-Yield:** The cAMP-PKA axis is the **canonical second messenger system** for glucagon action. This is frequently tested in NEET PG. ### Timeline of Glucose Elevation - **Glycogenolysis:** Dominant in first 30 minutes (rapid) - **Gluconeogenesis:** Becomes dominant after ~2 hours of fasting (sustained) **Clinical Pearl:** In prolonged fasting (>12 hours), hepatic glycogen is depleted and gluconeogenesis becomes the sole source of glucose production. ### Why Not Other Options? **Mnemonic for Glucagon's Actions: "GG-GOGO"** - **G**lucagon → **G**lycogenolysis + **G**luconeogenesis - **G**lucagon → **O**xidation of fats (↑ β-oxidation) - **G**lucagon → **O**pposite of insulin [cite:Guyton & Hall 14e Ch 79; Lehninger Principles of Biochemistry 8e Ch 23]