Gluconeogenesis: Keto's Unwanted Saboteur

Gluconeogenesis is a metabolic pathway that allows the body to create its own glucose from non-carbohydrate carbon sources. This process is particularly important for those on a low-carb or ketogenic diet, as it helps to maintain blood glucose levels and prevent hypoglycaemia. While gluconeogenesis is a necessary process, some people believe that it can interfere with ketosis and hinder weight loss. However, this is a misconception. Gluconeogenesis does not kick people out of ketosis, and it is not something to be feared. It is a normal and essential mechanism that ensures the body has enough glucose to function, even when carbohydrate intake is low.

Gluconeogenesis is a metabolic pathway that occurs in the liver and kidneys

During gluconeogenesis, the body makes glucose from non-carbohydrate carbon substrates. The main product from which glucose is made is pyruvate, a biological molecule involved in several energy-producing pathways. Pyruvate can be generated by breaking down amino acids like alanine and glutamate, known as glucogenic amino acids. It can also be produced through the breakdown of glycerol, a molecule released when adipose tissue is broken down into fatty acids, and lactate, which is always being produced at a low level, even when the body is at rest.

Gluconeogenesis is an important process for maintaining blood glucose levels, which typically range between 3.3 and 5.5mM (60-90mg/dl). If blood glucose falls below 2mM (about 36mg/dl), unconsciousness will occur. While on a typical diet, blood glucose is maintained by ingesting carbohydrates, those on a low-carb or ketogenic diet rely on gluconeogenesis to produce glucose.

During times of low energy availability, such as fasting or starvation, gluconeogenesis allows the body to create glucose from substrates circulating throughout the body, such as proteins from the breakdown of muscle tissue and compounds released during the breakdown of adipose tissue. Gluconeogenesis also plays a crucial role in maintaining blood glucose levels during a low-carbohydrate or ketogenic diet.

While most gluconeogenesis occurs in the liver, about 10% takes place in the kidneys. There are three crucial irreversible steps in the process that prevent a "futile cycle" where glucose is produced only to be broken down again. These steps are:

• The conversion of pyruvate to phosphoenol pyruvate (PEP) by pep carboxykinase
• Conversion of fructose 1,6-bisphosphate to fructose-6 phosphate by fructose 1,6-bisphosphatase
• Conversion of glucose 6-phosphate to glucose by glucose 6-phosphatase

In summary, gluconeogenesis is a metabolic pathway that occurs primarily in the liver but also in the kidneys. It allows the body to create glucose from non-carbohydrate sources, which is essential for maintaining blood glucose levels, especially during a low-carbohydrate or ketogenic diet.

It creates glucose from non-carb sources like lactate, glycerol and amino acids

Gluconeogenesis is a metabolic pathway that allows the liver and kidneys to make glucose from non-carbohydrate sources. This process is especially important when the body is not receiving glucose from external sources, such as during fasting, starvation, or a ketogenic diet.

The main non-carbohydrate sources used in gluconeogenesis are lactate, glycerol, and amino acids. Lactate is the major gluconeogenic substrate and is derived from pyruvate, which is the direct product of glucose or glycogen breakdown. During intense exercise, cells turn pyruvate into lactate, which can be used for energy and accumulates in the muscles. However, lactate can also be turned back into pyruvate and then into glucose through gluconeogenesis.

Glycerol is the third most used substrate and comes from fat breakdown. Glucogenic amino acids can also be used to make glucose, with alanine and glutamine being the main amino acids used. However, it is important to note that not all amino acids can be turned into glucose. Lysine and leucine, for example, are exclusively ketogenic. Additionally, it takes more amino acids to make glucose than it does to make ketones, which is why the body prefers to use ketones during a ketogenic diet.

Gluconeogenesis is necessary to prevent hypoglycaemia and death

Gluconeogenesis is a metabolic pathway that allows the body to create its own glucose from non-carbohydrate sources. This process is crucial for survival, especially when the body is in a state of low energy availability, such as during fasting or starvation. While a ketogenic diet can lead to a decrease in gluconeogenesis, it does not eliminate the body's need for glucose entirely.

During gluconeogenesis, the body converts non-glucose substances such as lactate, amino acids, and glycerol into glucose. This process typically occurs in the liver, with a small portion taking place in the kidneys. It is important for maintaining normal blood glucose levels, which typically range between 3.3 and 5.5 mM (60-90 mg/dl). If blood glucose falls below 2 mM (36 mg/dl), unconsciousness will occur. Therefore, gluconeogenesis plays a vital role in preventing hypoglycaemia, a state of dangerously low blood sugar that can have devastating consequences, including seizures, confusion, loss of consciousness, and even death.

In addition to preventing hypoglycaemia, gluconeogenesis is necessary for fuelling certain tissues in the body that rely solely on glucose for energy. These include red blood cells, the kidney medulla, the lens and cornea of the eye, and the testicles. These tissues lack the necessary transporters to utilise ketone bodies as fuel and, therefore, depend on gluconeogenesis to generate the glucose they need to function properly.

While a ketogenic diet may reduce the reliance on gluconeogenesis by promoting ketones as the preferred fuel source, it does not eliminate the need for this process entirely. Even on a ketogenic diet, some tissues will still require glucose, and gluconeogenesis will continue to occur to meet this need. Overall, gluconeogenesis is a necessary process that helps prevent hypoglycaemia and ensures the proper functioning of glucose-dependent tissues, ultimately helping to maintain overall health and well-being.

It's compatible with ketogenesis and doesn't kick you out of ketosis

Gluconeogenesis is compatible with ketogenesis and will not kick you out of ketosis. In fact, it's a crucial process that prevents hypoglycaemia and provides fuel for tissues that can't use ketones.

Gluconeogenesis is the process of creating glucose from non-carbohydrate sources, such as lactate, glycerol and certain amino acids. It occurs primarily in the liver and kidneys, and ensures that critical limits of glucose are maintained when carbohydrates are absent. This process is separate from glycolysis, which is the breakdown and extraction of energy from glucose.

Ketogenesis, on the other hand, is a metabolic pathway that produces ketone bodies, which serve as an alternative energy source for the body. Ketogenesis occurs when there is a decrease in carbohydrates or an increase in fatty acids, and is common in conditions such as starvation and type 1 diabetes.

While ketogenesis and gluconeogenesis are both chemical processes that provide energy when carbohydrate intake is low, they have distinct roles. Ketogenesis produces ketones to be used as fuel, while gluconeogenesis creates glucose. Importantly, ketogenesis does not completely replace gluconeogenesis, as some tissues, such as the kidney medulla and the brain, still require glucose to function optimally.

During ketosis, the body learns to use fat as its primary fuel source, with ketone bodies circulating in the blood providing energy. However, this does not mean that gluconeogenesis stops. In fact, during the initial days of a ketogenic diet, the body relies on gluconeogenesis to produce energy. Even after ketosis is established, gluconeogenesis continues at a lower rate to maintain glucose levels and prevent hypoglycaemia.

In summary, gluconeogenesis and ketogenesis are compatible processes that work together to ensure the body has the fuel it needs. Gluconeogenesis does not interfere with ketosis and is, in fact, necessary for optimal health during low-carbohydrate diets.

It's not caused by excess protein intake

Gluconeogenesis is a metabolic process that occurs in the liver and kidneys, where glucose is synthesised from non-carbohydrate sources such as lactate, pyruvate, glycerol, and certain amino acids (protein). This process is separate from glycolysis, the breakdown of glucose for energy, and is necessary for the body to maintain critical glucose levels when carbohydrates are absent from the diet.

While it is true that gluconeogenesis can occur when excess protein is consumed, it is not solely caused by this. The process can also occur during periods of fasting (such as when sleeping), starvation, or intense exercise. The body's preferred energy source is glucose, and it will use either glycolysis or gluconeogenesis to provide the body and brain with the energy needed to function.

During a low-carb diet, the body needs to make glucose from other sources, and gluconeogenesis is how it does this. However, this does not mean that consuming excess protein will keep the body from entering a state of ketosis, where fat is used as the primary energy source instead of glucose.

Ketosis is a metabolic state that differs from gluconeogenesis. Ketogenesis, the process of producing ketones to be used as fuel, occurs in the mitochondria of liver cells. While ketogenesis and gluconeogenesis are similar in that they provide energy when carbohydrates are not present in the diet, ketogenesis produces ketones instead of glucose.

The body can also use fat and ketones as fuel sources, which help preserve health and maintain muscle mass. However, the body doesn't use these right away, and it can take some time for the body to shift into ketosis. During the first three days of a ketogenic diet, stored glycogen and amino acids are the main fuel sources, with glycogen being the dominant source. Once glycogen is almost all used up, amino acids from food and muscle become the main fuel source.

Consuming excess protein can keep the body from entering ketosis because some amino acids found in protein cause insulin to be released after ingestion. Higher insulin levels limit the body's ability to enter ketosis because insulin keeps body fat and ketones from being used as energy. As a result, the liver will favour gluconeogenesis over ketogenesis.

However, it is important to note that restricting protein intake can also have negative consequences. Even when the body is primarily using fat and ketones for fuel, it still requires some glucose, which will come from either dietary protein or muscle mass. If protein intake is too low, the body will break down muscle mass, leading to a "skinny fat" physique where weight loss comes from muscle instead of fat.

Therefore, consuming the right amount of protein is critical. This will vary depending on activity level and body composition, but in general, sedentary individuals should aim for between 0.6g and 0.8g of protein per pound of lean body mass, while active individuals should aim for between 0.8g and 1.2g. It is also important to increase protein intake when restricting calories to ensure muscle maintenance.

In summary, while excess protein intake can contribute to gluconeogenesis, it is not the sole cause. The process is necessary for maintaining adequate glucose levels, especially during a low-carb diet or periods of fasting. Consuming the right amount of protein is critical to ensure the body can enter ketosis while preserving muscle mass.

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