Which substrate is the LEAST efficient for gluconeogenesis in the liver?

Explanation

## Gluconeogenic Substrates **Key Point:** Not all substrates can be used for gluconeogenesis. Fatty acids (except for the glycerol backbone of triglycerides) cannot be converted to glucose in mammals because acetyl-CoA, the end product of β-oxidation, cannot be converted back to pyruvate or other gluconeogenic precursors. ### Gluconeogenic Substrates in the Liver | Substrate | Entry Point | Efficiency | Notes | |-----------|-------------|-----------|-------| | **Lactate** | Pyruvate (via LDH) | High | Cori cycle; major substrate during exercise | | **Alanine** | Pyruvate (via transamination) | High | Glucose-alanine cycle; major substrate during fasting | | **Glycerol** | Glycerol-3-phosphate | Moderate | From triglyceride breakdown; enters glycolysis | | **Fatty acids** | Acetyl-CoA | **NONE** | Cannot form net glucose; acetyl-CoA cannot be converted to pyruvate | **High-Yield:** Acetyl-CoA is a **dead-end** for gluconeogenesis. The pyruvate dehydrogenase reaction is irreversible; there is no pathway to regenerate pyruvate from acetyl-CoA in animals. Fatty acids are therefore **NOT gluconeogenic** substrates. **Mnemonic:** **LAG** — Lactate, Amino acids, Glycerol are gluconeogenic. **FAT** is NOT — Fatty Acids (as acetyl-CoA) cannot form glucose. ### Why Fatty Acids Cannot Contribute to Gluconeogenesis 1. Fatty acids undergo β-oxidation → Acetyl-CoA 2. Acetyl-CoA enters the TCA cycle 3. The two carbons of acetyl-CoA are lost as CO₂ in the TCA cycle 4. No net synthesis of oxaloacetate or pyruvate occurs 5. **Result:** No glucose formation **Clinical Pearl:** During prolonged fasting, the body relies on amino acids and lactate for gluconeogenesis, not fatty acids. However, fatty acids provide energy (via ketone bodies) to spare glucose utilization in other tissues.