What Can Be Used for Gluconeogenesis in MCAT?

November 18, 2025 •

3 min read

During a fast lasting more than 24 hours, gluconeogenesis can provide up to 90% of the body's glucose supply to fuel organs like the brain. For success on the MCAT, a thorough understanding of exactly what can be used for gluconeogenesis, including its substrates and pathways, is essential for mastering metabolic questions.

Quick Summary

Gluconeogenesis is the metabolic pathway that synthesizes glucose from non-carbohydrate precursors like lactate, glycerol, and glucogenic amino acids, predominantly in the liver and kidneys.

Key Points

Major Precursors: The three primary substrates for gluconeogenesis are lactate, glycerol, and glucogenic amino acids.
Origin of Lactate: Lactate comes from anaerobic metabolism in exercising muscles and red blood cells and is converted to pyruvate in the liver via the Cori Cycle.
Glycerol's Entry: Glycerol from triglyceride breakdown in adipose tissue enters the pathway as dihydroxyacetone phosphate (DHAP) in the liver.
Glucogenic Amino Acids: All amino acids except leucine and lysine can be converted to glucose, entering the pathway via pyruvate or TCA cycle intermediates like oxaloacetate.
Non-glucogenic Sources: Even-chain fatty acids and ketogenic amino acids (leucine and lysine) cannot be used for the net synthesis of glucose.
Hormonal Control: Gluconeogenesis is stimulated by glucagon and inhibited by insulin, a reciprocal regulation that prevents futile cycling.

Introduction to Gluconeogenesis

Gluconeogenesis is a critical metabolic pathway that produces glucose from non-carbohydrate precursors, vital during fasting, starvation, or prolonged exercise when glycogen stores are low. This process maintains blood glucose levels for glucose-dependent tissues like the brain and red blood cells. Understanding its substrates and pathways is crucial for the MCAT.

The Major Gluconeogenic Substrates

The main sources of carbon for gluconeogenesis are lactate, glycerol, and glucogenic amino acids. This primarily occurs in the liver and renal cortex.

Lactate: The Cori Cycle

Lactate is produced during anaerobic glycolysis in exercising muscles and red blood cells. It travels to the liver, where it is converted back to pyruvate by lactate dehydrogenase. The Cori cycle involves the transport of lactate from muscle to liver, conversion to glucose, and the return of glucose to muscle.

Glycerol: The Lipid Backbone

Glycerol comes from the breakdown of triglycerides in adipose tissue. Unlike fatty acids, glycerol can be used for glucose synthesis. In the liver, glycerol is converted to dihydroxyacetone phosphate (DHAP), a glycolytic intermediate, via glycerol kinase and glycerol 3-phosphate dehydrogenase.

Glucogenic Amino Acids: Protein Power

During fasting, protein breakdown provides glucogenic amino acids, all except leucine and lysine. Their carbon skeletons enter the pathway at different points. Alanine and serine can convert to pyruvate. Glutamine forms alpha-ketoglutarate, an intermediate of the citric acid cycle. Other amino acids can form oxaloacetate. The glucose-alanine cycle involves alanine transport from muscle to the liver, conversion to pyruvate for gluconeogenesis, and glucose return to muscle.

Molecules That Cannot Be Used for Gluconeogenesis

It's important for the MCAT to know what molecules cannot be converted to glucose:

Even-Chain Fatty Acids: These produce only acetyl-CoA, which cannot be converted back to pyruvate due to the irreversible nature of pyruvate dehydrogenase. Carbons from acetyl-CoA are lost as CO2 in the citric acid cycle.
Ketogenic Amino Acids: Leucine and lysine are ketogenic, producing acetyl-CoA or acetoacetate, precursors for ketone bodies, but not glucose.

Comparison of Gluconeogenesis and Glycolysis


Feature	Gluconeogenesis	Glycolysis
Overall Purpose	Synthesize glucose	Break down glucose
Physiological State	Fasting, starvation, low-carb diet	Fed state, high blood glucose
Primary Location	Liver and kidneys	All cells with cytoplasm
Key Substrates	Lactate, glycerol, glucogenic amino acids	Glucose
Irreversible Steps	Bypass steps using unique enzymes	Unidirectional reactions
Key Enzymes	Pyruvate Carboxylase, PEPCK, Fructose-1,6-bisphosphatase, Glucose-6-phosphatase	Hexokinase/Glucokinase, Phosphofructokinase-1, Pyruvate Kinase
Energy Cost/Yield	Costs 6 ATP/GTP per glucose	Yields 2 ATP/NADH per glucose
Regulation	Stimulated by glucagon; inhibited by insulin	Stimulated by insulin; inhibited by glucagon

Hormonal and Allosteric Regulation

Gluconeogenesis is regulated to avoid a futile cycle with glycolysis.

Glucagon: Promotes gluconeogenesis during low blood glucose by activating key enzymes and inhibiting glycolysis.
Insulin: Inhibits gluconeogenesis when blood glucose is high by inactivating gluconeogenic enzymes.
Acetyl-CoA: Activates pyruvate carboxylase, directing pyruvate towards gluconeogenesis during fasting when fatty acid oxidation is high.

Conclusion

A strong understanding of gluconeogenesis is vital for the MCAT. Key takeaways include identifying the main substrates—lactate, glycerol, and glucogenic amino acids—and knowing which molecules (even-chain fatty acids, leucine, and lysine) cannot be used for net glucose synthesis. The regulation by hormones like insulin and glucagon and the specific enzymes involved in bypassing irreversible glycolytic steps are high-yield topics that connect various biochemical concepts. Mastering these aspects of gluconeogenesis is fundamental for tackling metabolism questions on the exam.

For further reading on this topic, consult the reliable information available on the Wikipedia page for Gluconeogenesis.

Frequently Asked Questions

The main carbon sources for gluconeogenesis are lactate, glycerol, and glucogenic amino acids. These precursors are converted into glucose primarily in the liver during states of fasting or low blood sugar.

Even-chain fatty acids cannot be used for the net synthesis of glucose in humans because their breakdown produces acetyl-CoA. The pathway from acetyl-CoA to pyruvate is irreversible, meaning the carbons cannot be incorporated into glucose. Odd-chain fatty acids are a minor exception, contributing via propionyl-CoA.

Ketogenic amino acids, specifically leucine and lysine, are catabolized into acetyl-CoA or acetoacetate. Since acetyl-CoA cannot be converted to pyruvate, these amino acids cannot contribute to a net glucose synthesis.

Lactate produced by anaerobic glycolysis in muscles is transported to the liver. In the liver, it is converted to pyruvate by lactate dehydrogenase. This pyruvate then serves as a substrate for gluconeogenesis, producing glucose that can be returned to the muscle, in a process known as the Cori cycle.

Hormones like glucagon, released during low blood glucose, promote gluconeogenesis. Insulin, released during high blood glucose, inhibits it. This reciprocal control ensures that glucose is either produced or consumed, but not both at the same time, preventing a 'futile cycle'.

Glycerol is the backbone of triglycerides. During lipolysis, glycerol is released into the blood and travels to the liver. There, it is phosphorylated and oxidized to dihydroxyacetone phosphate (DHAP), an intermediate of both glycolysis and gluconeogenesis, allowing it to be converted into glucose.

The primary site of gluconeogenesis is the liver. The kidneys also play a significant role, especially during prolonged fasting, and perform the process in their cortical region.