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Original Author(s): James Sheldon
Last updated: 8th April 2024
Revisions: 21

Original Author(s): James Sheldon
Last updated: 8th April 2024
Revisions: 21

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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.

Overview of Gluconeogenesis

Fig 1 – Diagram showing a summary of gluconeogenesis and glycolysis

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
  • Amino acids (mainly alanine).

Fig 2 – Diagram of the Cori cycle, 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, gluconeogenesis is the creation of glucose. However, it is not simply the reverse of glycolysis, as there are irreversible steps in glycolysis.

To circumvent this, some more enzymes are important in gluconeogenesis:

  • Phosphoenolpyruvate carboxykinase (PEPCK) converts oxaloacetate to phosphoenolpyruvate.
  • Fructose 1,6-bisphosphatase converts fructose 1,6-bisphosphate to fructose 6-phosphate.
  • Glucose-6-phosphatase converts glucose 6-phosphate into glucose.

Hormonal Control

Like glycolysis, this process is under the 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.