What is Gluconeogenesis?


Core Concepts

In this article, you will be able to define what is gluconeogenesis, explain its tissue-specific roles (e.g. liver vs skeletal muscle), outline several key enzymes involved, and compare it to glycolysis.

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Organisms, regardless of the domain of life in which they originate, share one commonality: each must maintain a constant internal balance, otherwise known as homeostasis. And mammals, such as humans, are no different.

An example of homeostasis would include surrounding the availability of glucose. For instance, human adults must maintain a blood glucose level from 70 mg/dL to 100 mg/dL through the breaking down of glycogen, a polymer of glucose, in the liver. Moreover, skeletal muscle must have ample glycogen at the ready to carry out ATP synthesis for the movement of the human body. However, what happens when these glucose stores are depleted? Well, the answer lies in gluconeogenesis.


It may be subdivided into its corresponding prefixes, suffixes, and roots.

  • gluco- = glucose
  • -neo- = new
  • -genesis = formation

Thus, it refers to the synthesis of glucose molecules from precursor molecules. One readily available precursor molecule is pyruvate. However, note others exist, such as lactate, glycerol, and several glucogenic amino acids.

A simplified view of gluconeogenesis with a pyruvate precursor.


It begins in the mitochondrial matrix and ends in the cytosol of eukaryotic cells, primarily in the liver and skeletal muscle.

Two primary organs involved in gluconeogenesis: the liver and skeletal muscle.


It primarily occurs in the liver and the skeletal muscle in response to perturbations of homeostasis. If blood sugar drops below homeostatic levels, the liver increases the rate of gluconeogenesis to compensate. However, if blood sugar rises above homeostatic levels, the liver decreases the rate of gluconeogenesis to give the body time to store it.

If the glucose stores in the skeletal muscle drops during times of intense activity, the skeletal muscle increases the rate of gluconeogenesis to create energy. However, if glucose stores are ample in amount, the rate of gluconeogenesis decreases as it would be unnecessary to waste resources on something already high in amount.


It begins with pyruvate. However, it is critical to reference the structure of where it resides: the mitochondrion. While the outer membrane of the mitochondrion is relatively porous, the inner membrane is relatively impermeable, problematizing the transport of pyruvate into the cytosol.

Thus, one of the enzymes of gluconeogenesis converts the initial substrate, pyruvate, into oxaloacetate. Oxaloacetate may be converted into malate through malate dehydrogenase, allowing it to leave through a malate-specific transporter. Once in the cytosol, it may be converted back into oxaloacetate and proceed through the gluconeogenesis pathway.

Gluconeogenesis originating in the mitochondrial matrix. Pyruvate is converted into oxaloacetate, which can be converted into malate and be exported.

From here, three additional enzymes are required to carry out the conversion. This process is contrary to glycolysis. While glycolysis is a catabolic (breaking down) process, gluconeogenesis is an anabolic (building up) process. This process requires three additional enzymes to compensate for the three irreversible enzymes of glycolysis.

  • Hexokinase is replaced with glucose-6-phosphatase
  • PFK-1 is replaced with fructose-1,6-bisphosphatase (FBPase-1)
  • Pyruvate kinase is replaced with PEP carboxykinase

The three most distinctive steps of gluconeogenesis which occur in the cytosol, with their substrates and enzymes.

What is Gluconeogenesis? Practice Problems

Problem 1

Compare and contrast the tissue-specific function of gluconeogenesis in the liver and in skeletal muscle.

Problem 2

Explain why pyruvate produced in the mitochondrial matrix cannot simply export through the inner mitochondrial membrane.

Problem 3

A specialized glucose transporter, known as GLUT 4, is selectively translocated to the cell membrane of skeletal muscle in the presence of insulin to encourage the uptake of glucose. If a mutation prevented the transcription and translation of a viable GLUT 4 transporter, would the rate of gluconeogenesis in skeletal muscle increase, decrease, or remain the same?

What is Gluconeogenesis? Practice Problem Solutions

Problem 1

While gluconeogenesis in the liver helps regulate blood glucose levels, gluconeogenesis in skeletal muscle helps produce energy in the form of ATP.

Problem 2

The inner mitochondrial membrane has no specific transporter protein to export pyruvate out of the matrix. If it did, this would complicate glycolysis. Thus, it must be converted into oxaloacetate first, which can be converted into malate and exported through malate-specific transporters to continue gluconeogenesis.

Problem 3

Gluconeogenesis would increase.

Further Reading

We recommend reading this article to learn more on the topic!