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Original Author(s): James Sheldon
Last updated: 28th March 2022
Revisions: 19

Original Author(s): James Sheldon
Last updated: 28th March 2022
Revisions: 19

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Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol and glucogenic amino acids. This article will discuss the process of gluconeogenesis as well as relevant clinical conditions that may occur when something goes wrong.

Overview of Gluconeogenesis

Fig 1 – Overview of the gluconeogenesis pathway

Process of Gluconeogenesis

Gluconeogenesis occurs after around 8 hours of fasting, when liver glycogen stores start to deplete and an alternative source of glucose is required. It occurs mainly in the liver and to a lesser extent in the cortex of the kidney. There are three main precursors: lactate from anaerobic glycolysis in exercising muscle and red blood cells via the Cori Cycle, glycerol released from the breakdown of triglycerides in adipose tissue and amino acids (mainly alanine).

Fig 2 – Diagram of the Cori cyle, showing how lactate is generated by muscles and then used by gluconeogenesis.

Gluconeogenesis has a close relationship to glycolysis. Whilst glycolysis is the breaking of glucose, gluconeogensis is the creation of glucose. However, gluconeogenesis is not simply the reverse of glyolysis, as there are irreversible steps in glycolysis.

To circumvent this, some more enzymes are important in gluconeogensis, such as phosphoenolpyruvate carboxykinase (PEPCK) which converts oxaloacetate to phosphoenolpyruvate. Fructose 1,6-bisphosphatase is also important, converting fructose 1,6-bisphosphate to fructose fructose 6-phosphate. Finally, glucose-6-phosphatase turns glucose 6-phosphate into glucose.

Fig 3 – Diagram demonstrating the 3 steps that differ in gluconeogensis and glycolysis.

Hormonal Control

Gluconeogenesis, like glycolysis, is under tight control of hormones to regulate blood glucose. Stress hormones such as glucagon or cortisol upregulate PEPCK and fructose 1,6-bisphosphatase in order to stimulate gluconeogenesis. However, in a fed, high energy state gluconeogenesis decreases by inhibiting PEPCK and fructose 1,6-bisphosphatase.

Clinical Relevance – Diabetes Mellitus

Gluconeogenesis is one the major contributors to the hyperglycaemia seen in diabetic patients as cells ‘feel’ starved of nutrients and so send out hormonal signals to increase glucose levels in the blood via gluconeogenesis.

Clinical Relevance – Alcohol-Related Hypoglycaemia

Alcohol abuse alters the NAD+/NADH ratio, leading to excess NADH. This inhibits fatty acid oxidation that provides ATP and favours the pyruvate to lactate reaction, depleting the supply of pyruvate for gluconeogenesis and causing hypoglycaemia. This leads to hepatic glycogen depletion combined with alcohol-mediated inhibition of gluconeogenesis and is common in malnourished alcohol abusers.