Maintaining stable blood glucose levels is a critical metabolic priority for the human body, essential for the continuous function of anaerobic tissues like red blood cells and, most importantly, the brain. While dietary carbohydrates and hepatic glycogen stores provide a short-term supply, the body must generate its own glucose during periods of prolonged fasting, starvation, or intense exercise. This vital process is known as gluconeogenesis: the de novo synthesis of glucose from non-carbohydrate precursors.
This article provides a comprehensive overview of all the major substrates for gluconeogenesis. We will explore the three primary precursors—lactate, glucogenic amino acids, and glycerol—as well as other contributors, tracing their metabolic journeys from peripheral tissues like muscle and adipose to their ultimate conversion into glucose in the liver and kidneys.
Gluconeogenesis produces glucose from non-carbohydrate sources like lactate, glycerol, and glucogenic amino acids. The main substrates for gluconeogenesis are:
1- Lactate
Lactate is converted to pyruvate by the enzyme lactate dehydrogenase in the cytosol of liver or kidney cells, producing NADH. Pyruvate is then converted to glucose by gluconeogenesis.
In muscle cells, lactate is produced from glucose metabolism under anaerobic conditions. Lactate enters the bloodstream and is carried to the liver. The gluconeogenesis pathway converts lactate into pyruvate and glucose in the liver. The glucose produced is reabsorbed into the blood and transported back to the muscles for energy production. This cycle is known as the Cori cycle.
2- Alanine
Alanine is typically produced from the transamination of pyruvate in muscle cells. After entering liver cells, alanine transaminase (ALT) converts alanine to pyruvate. Pyruvate is converted to glucose, as described in the reactions. Alanine is transported from the muscles to the liver to remove amino groups from the body.
3- Glycerol
Glycerol kinase enzyme is only found in liver and kidney tissues. The enzyme is essential for glycerol metabolism. Glycerol is initially phosphorylated by glycerol kinase to enter the gluconeogenesis pathway.
Glycerol is converted to glycerol-3-phosphate. In this reaction, one molecule of ATP is consumed. Glycerol 3-phosphate is converted to dihydroxyacetone phosphate by glycerol 3-phosphate dehydrogenase, an intermediate in the gluconeogenesis pathway. One molecule of NADH is produced in the reaction catalyzed by glycerol 3-phosphate dehydrogenase.
4- Propionate
Propionate is the primary source of glucose in ruminants. This fatty acid is released into the blood after being produced by microorganisms in the rumen. Propionate is converted to propionyl-CoA by the enzyme acyl-CoA synthetase in liver cells, using one molecule of CoA.
In this reaction, one molecule of ATP is broken down into AMP + PPi. Propionyl-CoA is carboxylated by propionyl-CoA carboxylase to produce D-methylmalonyl-CoA. This enzyme needs biotin to function. In this reaction, one ATP molecule is consumed. D-methylmalonyl-CoA is isomerized to L-methylmalonyl-CoA by the enzyme racemase. L-methylmalonyl-CoA is converted to succinyl-CoA by the isomerase enzyme. Succinyl-CoA enters the Krebs cycle and is converted to malate, an intermediate in the gluconeogenesis pathway.
Conclusion
Gluconeogenesis is a vital metabolic process for maintaining blood glucose homeostasis, especially during fasting or metabolic stress. Reviewing all substrates highlights the remarkable flexibility of cells to synthesize glucose from diverse sources, including lactate, glycerol, glucogenic amino acids, and pyruvate. This metabolic adaptability not only plays a central role in energy balance but also reflects the intricate regulation of enzymatic pathways. A comprehensive understanding of these substrates and their interplay may provide valuable insights for developing therapeutic strategies for metabolic disorders such as diabetes and liver diseases.
This article was reviewed for accuracy by Dr. Mosayeb Rostamian. The content is based on current scientific evidence and is intended for educational purposes only.
Reference
- Nelson, D. L., Cox, M. (2021). Principles of Biochemistry. United States: W. H. Freeman.
- Rodwell, V. W., Bender, D., Botham, K. M., Kennelly, P. J., Weil, P. A. (2018). Harper’s Illustrated Biochemistry Thirty-First Edition. United States: McGraw Hill LLC.
- Chourpiliadis, Charilaos, and Shamim S. Mohiuddin. “Biochemistry, Gluconeogenesis.” StatPearls, StatPearls Publishing, 2025. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK544346/.
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Melkonian EA, Asuka E, Schury MP. Physiology, Gluconeogenesis. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2025. PMID: 31082163.
