Gluconeogenesis is a metabolic pathway for making the sugar glucose from non-carbohydrate sources of carbon. For humans, it’s one way the body makes glucose to provide energy to cells without you having to actually eat any sugar or other carbohydrate. However, many other types of living organisms use gluconeogenesis, including other animals, plants, fungi, and bacteria. Here’s what you need to know about gluconeogenesis.
Gluconeogenesis Definition
The word “gluconeogenesis” means “making new glucose.” There are a few different ways of making glucose, which is the main sugar used for energy. But, gluconeogenesis starts with non-carbohydrate sources of carbon, mainly from fats and protein. Fats (lipids and odd-chain fatty acids) enter the pathway by getting broken into glycerol and lactate. Ketone bodies provide acetone for the process. Proteins break into glucogenic amino acids (mainly alanine and glutamine).
What Is the Main Function of Gluconeogenesis?
The main function of gluconeogenesis is providing glucose to cells. Essentially, its function is maintaining normal blood sugar levels.
Humans typically get all the glucose we need from carbohydrates in our diet. So, gluconeogenesis comes into play during intense exercise, low-carb dieting, fasting, or starvation. Gluconeogenesis is not the only process that produces glucose. Another mechanism is glycogenolysis, which breaks down glycogen stored by the liver into glucose.
However, some other organisms perform gluconeogenesis all the time. For example, cattle and other ruminants rely on gluconeogenesis for glucose because the microorganisms in their rumen (first stomach) absorb sugars from food.
Where Does It Occur?
The location of the process depends on the species. In humans, gluconeogenesis mainly occurs in the liver, with smaller quantities of glucose produced in the kidney, intestine, muscle, and brain. Each organ uses slightly different precursor molecules. For example, the liver uses lactate, glycerol, and glucogenic amino acids (primarily alanine). The kidney mainly starts with lactate, glycerol, and the amino acid glutamine. The pathway typically begins within the mitochondria and within the cytoplasm of the cells.
Gluconeogenesis Pathway
The gluconeogenesis pathway mainly is a reversal of the step in glycolysis, the process that metabolizes glucose. However, it replaces three endergonic reactions with more energetically-favorable reactions. Here is an overview of the steps in the pathway:
- In the mitochondria, the carboxylation of pyruvate forms oxaloacetate. The enzyme pyruvate carboxylase catalyzes the reaction, which requires 1 ATP. High levels of glucose or ADP inhibit this reaction.
- Oxaloacetate gets reduced to malate. This step uses NADH. The step transports the molecule outer of the mitochondria.
- In the cytosol, malate gets oxidized back to oxaloacetate using NAD+. The remaining steps also occur within the cytosol.
- Decarboxylation and phosphorylation of oxaloacetate form phosphoenolpyruvate. The reaction uses the enzyme PEPCK and hydrolyzes 1 GTP to 1 GDP.
- Now, the process follows the reverse of glycolysis, except fructose 1,6-biphosphatase converts fructose 1,6-biphosphate into fructose 6-phosphate, using 1 H2O and releasing 1 phosphate. This the rate-limiting step in the process.
- Phosphoglucoisomerase changes glucose-6-phosphate into fructose-6-phosphate.
- Within the lumen of the endoplasmic reticulum, the enzyme glucose-6-phosphatase hydrolyzes glucose-6-phosphate into glucose. The reaction releases one inorganic phosphate.
Is Gluconeogenesis Catabolic or Anabolic?
Gluconeogenesis is an example of an anabolic process. In anabolism, a metabolic pathway makes a molecule (glucose, in this case) from simpler ones. Glycolysis, in contrast, is a catabolic process because it breaks up glucose to supply cells with energy.
How Does Insulin Affect Gluconeogenesis?
Insulin inhibits gluconeogenesis. However, it does not suppress the process properly in individuals with compromised insulin signaling, such as type 2 diabetes or metabolic syndrome. This leads to hyperglycemia (high blood sugar).
Does Glucagon Affect Gluconeogenesis?
Glucagon stimulates gluconeogenesis in the liver. It increases acetyl-CoA, pyruvate carboxylase flux, and mitochondrial fat oxidation. One reason understanding the process is important is because controlling the ratio of insulin to glucagon in the liver offers a way of overcoming insulin resistance for people with nonalcoholic fatty liver disease, metabolic syndrome, or type 2 diabetes.
References
- Beitz, D.C. (2004). “Carbohydrate metabolism.”. In Reese WO (ed.). Dukes’ Physiology of Domestic Animals (12th ed.). Cornell Univ. Press. ISBN 978-0801442384.
- de Figueiredo, L.F.; Schuster, S.; Kaleta, C.; Fell, D.A. (January 2009). “Can sugars be produced from fatty acids? A test case for pathway analysis tools”. Bioinformatics. 25 (1): 152–8. doi:10.1093/bioinformatics/btn621
- Hatting, Maximilian; Tavares, Clint; et al. (2018). “Insulin regulation of gluconeogenesis.” Ann. NY Acad. Sci. 1411(1): 21-35. doi:10.1111/nyas.13435
- Nelson, D.L.; Cox, M.M. (2000). Lehninger Principles of Biochemistry. USA: Worth Publishers. ISBN 978-1-57259-153-0.
- Nuttall, F.Q.; Ngo, A.; Gannon, M.C. (September 2008). “Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant?”. Diabetes/Metabolism Research and Reviews. 24 (6): 438–58. doi:10.1002/dmrr.863
- Perry, Rachel J.; Zhang, Dongyan; et al. (2020). “Glucagon stimulates gluconeogenesis by NSP3R1-mediated hepatic lipolysis.” Nature. 579: 279-283. doi:10.1038/s41586-020-2074-6
- Yip. J.; Geng, X.; Shen, J.; Ding, Y. (2017). “Cerebral Gluconeogenesis and Diseases”. Frontiers in Pharmacology. 7: 521. doi:10.3389/fphar.2016.00521