Gluconeogenesis: Function, Role & Diseases

Gluconeogenesis ensures the re-synthesis of glucose from pyruvate, lactate and glycerol in the body. In this way, it ensures the glucose supply of the organism during periods of starvation. Disturbances in gluconeogenesis can lead to dangerous hypoglycemia.

What is gluconeogenesis?

Gluconeogenesis reactions occur mainly in the liver and muscles. During gluconeogenesis, glucose is produced again from the breakdown products of protein, carbohydrate, and fat metabolism. The reactions for gluconeogenesis take place mainly in the liver and in the muscles. There, the synthesized glucose is then condensed into glucogen, a storage substance that serves as an energy store for the rapid supply of energy to nerve cells, erythrocytes and muscles. Gluconeogenesis can produce 180 to 200 grams of new glucose per day. Gluconeogenesis can be viewed as a reversal of glycolysis (breakdown of glucose) to pyruvate or lactate, but three reaction steps must be replaced by bypass reactions for energy reasons. Glycolysis produces pyruvate (pyruvic acid) or, under anaerobic conditions, lactate (anion of lactic acid). Furthermore, pyruvic acid is also formed from amino acids during their degradation. Another substrate for the reconstitution of glucose is glycerol, which is derived from fat degradation. It is converted to dihydroxyacetone phosphate, which acts as a metabolite in the synthesis chain of gluconeogenesis to build glucose.

Function and role

The question arises as to why glucose should be rebuilt when it was previously broken down by glycolysis for energy production. However, it must be remembered that nerve cells, the brain, or erythrocytes are compellingly dependent on glucose as a source of energy. If the body’s glucose reserves are depleted without being replenished quickly enough, the result is dangerous hypoglycemia, which can even be fatal. With the help of gluconeogenesis, normal blood glucose levels can be kept constant even during periods of starvation or in energy-consuming emergency situations. One third of the newly synthesized glucose is stored as glucogen in the liver and two thirds in skeletal muscle. During a prolonged period of starvation, the demand for glucose decreases somewhat because the utilization of ketone bodies for energy production is established as a second metabolic pathway. The central role in gluconeogenesis is played by pyruvic acid (pyruvate) or the lactic acid (lactate) formed from it under anaerobic conditions. Both compounds are also degradation products during glycolysis (sugar breakdown). In addition, pyruvate is also formed during the breakdown of amino acids. At another point, glycerol from fat breakdown can also be converted into a metabolite of gluconeogenesis, being incorporated into this process. Thus, gluconeogenesis produces glucose again from the breakdown products of carbohydrate, protein, and fat metabolism. The body’s own regulatory mechanisms ensure that gluconeogenesis and glycolysis do not run side by side to the same extent. When glycolysis is enhanced, gluconeogenesis is somewhat attenuated. In a phase of increased gluconeogenesis, glycolysis is in turn throttled. Hormonal regulatory mechanisms exist in the organism for this purpose. For example, if a lot of carbohydrates are supplied through food, the blood glucose level rises. At the same time, the production of insulin in the pancreas is stimulated. Insulin ensures that glucose is supplied to the cells. There, it is either broken down to produce energy or, if energy requirements are low, converted into fatty acids that can be stored as triglycerides (fat) in adipose tissue. When there is an undersupply of carbohydrates (hunger, an extremely low-carbohydrate diet or high glucose consumption in emergencies), the blood glucose level initially drops. This calls on insulin‘s hormonal counterpart, the hormone glucagon. Glucagon induces the breakdown of stored glucogen in the liver to glucose. When these stores are depleted, increased gluconeogenesis from amino acids starts to re-synthesize glucose if starvation continues in the body.

Diseases and ailments

When gluconeogenesis is disrupted, the body may experience hypoglycemia (low blood sugar). Hypoglycemia can have many causes.Thus, hormonal regulatory mechanisms lead to increased gluconeogenesis in the case of increased glucose demand or reduced carbohydrate intake. The hormonal counterpart of insulin is the hormone glucagon. When blood glucose levels fall, glucagon production increases, which then prompts increased gluconeogenesis. First, glucogen stored in the liver and muscles is broken down and converted to glucose. When all glucogen reserves are depleted, glucogenic amino acids are converted to glucose. Thus, muscle breakdown takes place to supply the body with energy. However, if gluconeogenesis is difficult to start for various reasons, hypoglycemia develops, which in severe cases can lead to unconsciousness and even death. For example, liver diseases or certain medications can hinder gluconeogenesis. Alcohol consumption also inhibits gluconeogenesis. Severe hypoglycemia is an emergency that requires rapid medical attention. Another gluconeogenesis-promoting hormone is cortisol. Cortisol is a glucocorticoid of the adrenal cortex and functions as a stress hormone. Its function is to quickly provide energy during stressful physical situations. To do this, the body’s energy reserves must be activated. Cortisol stimulates the conversion of amino acids in the skeletal muscles into glucose as part of gluconeogenesis. If the adrenal cortex is overactive, for example due to a tumor, too much cortisol is constantly produced. Gluconeogenesis then runs at full speed. In this process, the overproduction of glucose leads to muscle breakdown, weakening of the immune system and truncal obesity. This clinical picture is known as Cushings syndrome.