Gluconeogenesis – creation of glucose

What is gluconeogenesis?

Gluconeogenesis is the body's method of producing glucose when carbohydrate supplies are low. It is a critical process that ensures stable blood sugar levels and supplies organs such as the brain, red blood cells and kidneys with energy.

This process occurs primarily in the liver, but also in the kidneys, and uses non-carbohydrate sources as substrates. These sources include amino acids (particularly alanine and glutamine from muscle tissue), lactate (from anaerobic glycolysis in muscle or red blood cells), and glycerol (from the breakdown of triglycerides in adipose tissue).

Gluconeogenesis in ketosis versus non-ketosis

What makes gluconeogenesis extra interesting is how the process varies depending on the body's metabolism.

In a non-ketogenic state, where the body has access to carbohydrates, the diet covers most of the need for glucose. Here, gluconeogenesis is minimal, and any needs are often met by the breakdown of muscle to obtain amino acids. Insulin levels in such a state are higher, which inhibits the release of fatty acids from adipose tissue and thus reduces the supply of glycerol. In this case, eating meat can cause a significant increase in blood sugar.

In ketosis, however, everything changes.

When carbohydrate intake is very low, the body switches to fat burning as a primary energy source. Ketones, which are produced from fatty acids, cover a significant portion of the energy needs of the brain and muscles. There are only a very few cells that absolutely need glucose as fuel and cannot use ketones instead. This dramatically reduces the need for glucose, and thus also the intensity of gluconeogenesis.

In this case, blood sugar does not rise when you eat meat, but remains steady, at the level the body desires.

Glycerol, released by the breakdown of fat, now becomes a major source of glucose, while muscle proteins are spared to a much greater extent. This adaptation is one of the reasons why many people experience stable energy and less muscle catabolism during a ketogenic diet.

Regulation of gluconeogenesis

Hormones play a crucial role in controlling gluconeogenesis.

Glucagon and cortisol stimulate the process by upregulating key enzymes such as PEPCK, while insulin acts in the opposite way and inhibits the process by reducing substrate availability and enzyme activity. In ketosis, where insulin levels are very low, gluconeogenesis is given more freedom, but energy needs are mainly met by ketone bodies.

This creates a balanced state where the body adapts to a fat-based fuel.

In other words, gluconeogenesis is a flexible and adaptable process that ensures the body's survival in different situations. Whether you are in ketosis or not, this acts as a mechanism that always prioritizes maintaining balance.

More technical: How does gluconeogenesis take place?

Gluconeogenesis starts with the substrates to be converted to glucose. Lactate is converted to pyruvate through the enzyme lactate dehydrogenase, while amino acids such as alanine enter the process by being converted to pyruvate or intermediates in the citric acid cycle.

Glycerol from adipose tissue is first converted to glycerol-3-phosphate, which is then converted to dihydroxyacetone phosphate (DHAP), a molecule that can participate directly in gluconeogenesis.

Although the process resembles glycolysis in reverse, there are three steps that cannot be run in reverse. These require specific bypass reactions to proceed. Pyruvate is first converted to oxaloacetate in the mitochondria by pyruvate carboxylase, before being converted to phosphoenolpyruvate (PEP) by the enzyme PEPCK. Another important step is the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate by the enzyme fructose-1,6-bisphosphatase. Finally, glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose, allowing glucose to be released into the blood.

This is an energy-intensive process. For each unit of glucose produced, six molecules of ATP or GTP are required. This means that the body only uses gluconeogenesis when it is truly necessary.

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