Gluconeogenesis – Pathway, Significance, and Regulation

Gluconeogenesis is the process in which glucose is formed and involves a series of Gluconeogenesis steps and specific Gluconeogenesis enzymes in its pathway. Understanding the Gluconeogenesis definition helps comprehend how it occurs in particular organs and tissues.

Gluconeogenesis occurs in the liver and kidneys. The gluconeogenesis pathway helps maintain blood glucose levels during fasting or low carbohydrate intake. The gluconeogenesis significance is that controls blood sugar levels during deprivation.

In this article, we will cover the gluconeogenesis cycle, its significance, pathway, and more.

Gluconeogenesis Meaning

Gluconeogenesis is the process in which the non-carbohydrate molecule like lactate, glycerol, and some amino acids are converted into glucose.

When nutritional intake is inadequate or absent, fresh glucose is created from non-carbohydrate precursors (or gluconeogenic precursors) like lactate, glycerol, and some amino acids through gluconeogenesis. The gluconeogenesis pathway is also necessary for the management of acid-base balance and the synthesis of structural components obtained from carbohydrates.

This process is carried out oppositely glycolysis. Another name for it is neo-glucogenesis. It is a common route shared by all living things, including people, animals, plants, fungi, and other species.

Gluconeogenesis Occurs in – Gluconeogenesis  Location

Gluconeogenesis primarily occurs in the liver and to a lesser extent in the kidneys of vertebrates. These organs contain the necessary enzymes and metabolic machinery to synthesize glucose from non-carbohydrate precursors. The liver, being a central metabolic organ, plays a crucial role in regulating blood glucose levels and ensuring a steady supply of glucose to other tissues, especially during fasting or prolonged periods of carbohydrate restriction. The kidneys contribute to gluconeogenesis by producing glucose from precursors such as lactate, glycerol, and amino acids, although to a lesser extent compared to the liver.

Features of Gluconeogenesis 

Some of the important features of gluconeogenesis are given below:

• Although it mostly affects the liver, it can also exist in trace amounts in the small intestine and kidney.
• The little precursor molecules combine to form a high-energy result like glucose, which is why gluconeogenesis is also known as the “Endogenous Glucose pathway.”
• Gluconeogenesis is an essential cycle that generates glucose, which is required for all catabolic processes and for maintaining life.
• Any non-carbohydrate substances that can be converted to pyruvate or glycolysis intermediates can serve as a source of substrates for gluconeogenesis in humans.
• A route from fatty acids to glucose can be provided by acetone, which is produced from ketone bodies when there is a protracted period of fasting.
• Even though the liver is where most gluconeogenesis takes place, diabetes and extended fasting increase the proportional contribution of the kidney to gluconeogenesis.
• Up until it is connected to the breakdown of ATP or GTP, when the gluconeogenesis pathway is essentially exergonic.

Gluconeogenesis Pathway

A pathway called “gluconeogenesis” consists of eleven enzyme-catalyzed events in succession. Depending on the substrate being utilized, the route will either start in the mitochondria or cytoplasm of the liver or the kidney cortex cells. Many of the reactions are the reversal of glycolysis processes.

• The cytoplasm or mitochondria of the liver or kidney are where glucose synthesis begins. Two pyruvate molecules must first carboxylate in order to create oxaloacetate. One ATP (energy) molecule is needed for this.
• Oxaloacetate is changed into malate by NADH so that it may leave the mitochondria.
• After leaving the mitochondria, malate is converted back to oxaloacetate by oxidation.
• Oxaloacetate is transformed into phosphoenolpyruvate by the enzyme Phosphoenolpyruvate carboxykinase (PEPCK).
• Phosphoenolpyruvate is changed into fructose 1,6-bisphosphate by reversing glycolytic activities.
• Fructose-1,6-bisphosphatase catalyzes the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate in the process that releases inorganic phosphate.
• Fructose-6-phosphate is changed into glucose-6-phosphate by the enzyme phosphohexose isomerase.
• Glucose-6-phosphate causes the synthesis of inorganic phosphate, which releases free glucose into circulation. An enzyme called glucose 6-phosphatase is at work here.

In Mitochondria

Pyruvate + ATP → Oxaloacetate + ADP + Pi

Oxaloacetate + NADH → Malate + NAD+

The molecule can exit mitochondria mainly by conversion to malate. In the cytoplasm, it is changed back to oxaloacetate.

In Cytoplasm

Malate + NAD+ → Oxaloacetate + NADH

Oxaloacetate + GTP → PEP + GDP

Following that, it goes through the same intermediaries as glycolysis. The last reaction occurs in the endoplasmic reticulum.

In Endoplasmic Reticulum

G6P → glucose (catalyst: glucose-6-phosphatase)

A glucose transporter moves glucose from the cell and into the extracellular space.

Gluconeogenesis Cycle

The key steps in the gluconeogenesis cycle include:

1. Conversion of Pyruvate to Phosphoenolpyruvate (PEP): Pyruvate, derived from lactate or other non-carbohydrate sources, is carboxylated to form oxaloacetate, which is then decarboxylated and phosphorylated to generate PEP.
2. Conversion of Fructose-1,6-Bisphosphate to Fructose-6-Phosphate: Fructose-1,6-bisphosphate is converted to fructose-6-phosphate through a series of enzymatic reactions, bypassing the irreversible steps of glycolysis.
3. Conversion of Glucose-6-Phosphate to Glucose: Glucose-6-phosphate is dephosphorylated to produce glucose, which can be released into the bloodstream for use by other tissues.

Gluconeogenesis Pathway Diagram

The labelled diagram of Gluconeogenesis pathway is goven below:

Gluconeogenesis

What are the 4 key Enzymes of Gluconeogenesis?

The four key enzymes involved in the process of gluconeogenesis are:

1. Pyruvate carboxylase: This enzyme converts pyruvate to oxaloacetate, a key intermediate in gluconeogenesis, in the mitochondria.
2. Phosphoenolpyruvate carboxykinase (PEPCK): PEPCK catalyzes the conversion of oxaloacetate to phosphoenolpyruvate (PEP) in the cytoplasm, an important step in bypassing the irreversible reaction of glycolysis.
3. Fructose-1,6-bisphosphatase (FBPase): FBPase hydrolyzes fructose-1,6-bisphosphate to fructose-6-phosphate, allowing the reversal of the glycolytic pathway.
4. Glucose-6-phosphatase (G6Pase): G6Pase converts glucose-6-phosphate to glucose, facilitating its release into the bloodstream for use by other tissues. These enzymes collectively enable the synthesis of glucose from non-carbohydrate precursors, ensuring a steady supply of glucose for energy production in the body.

Gluconeogenesis of Amino acids

The amino acids that can be transformed into glucose are known as gluconeogenic amino acids. Most of them are either deaminated or transaminated into the intermediates of the citric acid cycle. As a result, around 20 amino acids enter the TCA cycle; some produce only one intermediate (such as alanine), while others produce two intermediates (example- Phenylalanine). As a result, amino acids go through the metabolic pathway via phosphoenol pyruvic acid, oxalo acetic acid, and glucose.

Regulation of Gluconeogenesis

Although the majority of the steps in gluconeogenesis are the opposite of those in glycolysis, three tightly controlled and powerfully endergonic processes are swapped out for more kinetically advantageous ones.

• The glycolysis enzymes glucose-6-phosphatase, fructose-1,6-bisphosphatase, and PEP carboxykinase/pyruvate carboxylase are used in place of hexokinase/glucokinase, phosphofructokinase, and pyruvate kinase.
• Usually, comparable chemicals that control these enzymes have opposing effects.
• For instance, acetyl CoA and citrate block the glycolytic enzyme pyruvate kinase while activating the gluconeogenesis enzymes pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively. This mechanism of reciprocal regulation allows glycolysis and gluconeogenesis to counteract one another, preventing a pointless loop in which glucose is synthesized just to be broken down.
• The only gluconeogenic enzymes absent from the cytosol are the mitochondrial pyruvate carboxylase and, in mammals, phosphoenolpyruvate carboxykinase.
• The pace of gluconeogenesis is ultimately controlled by the primary enzyme fructose-1,6-bisphosphatase, which is also controlled by cAMP and its phosphorylation through signal transduction.
• Globally, gluconeogenesis is regulated by the hormone glucagon, which is produced when blood sugar levels are low. Insulin inhibits gluconeogenesis to counterbalance glucagon. Excess glucagon and insulin resistance are characteristics of type 2 diabetes.
• Metformin, an anti-diabetic medication, overcomes insulin’s inability to suppress gluconeogenesis because of insulin resistance by predominantly inhibiting gluconeogenesis.
• According to studies, the regulation of fasting plasma glucose levels is not significantly impacted by the absence of hepatic glucose synthesis.

Importance of Gluconeogenesis

Significance of Gluconeogenesis are given below:

• The gluconeogenesis cycle is crucial for controlling blood sugar levels during deprivation.
• RBCs, neurons, skeletal muscle, the medulla of the kidney, the testes, and embryonic tissue are just a few of the cells and tissues that need glucose to function.
• The Neoglucogenesis cycle clears the blood of compounds like glycerol and lactate, which are generated by muscles and RBCs, respectively (produced from adipose tissue).
• Glycogenolysis is the breakdown of glycogen, the principal carbohydrate stored in animal liver and muscle cells, into glucose to give immediate energy while fasting and to keep blood sugar levels stable.

Difference Between Gluconeogenesis and Glycogenolysis

The key differences between the gluconeogenesis and glycogenolysis are given below:

Insulin Resistance

Insulin resistance occurs when cells in our muscles, fat, and liver fail to respond to insulin and are unable to utilize glucose from our blood for energy. To compensate, your pancreas produces extra insulin. Our blood sugar levels rise over time. Obesity, high blood pressure, high cholesterol, and type 2 diabetes are all symptoms of insulin resistance syndrome. It might impact one in every three Americans. It is also referred to as a metabolic syndrome.

Reversing Insulin Resistance

• If you have insulin resistance, you want to become insulin sensitive (cells are more effective at absorbing blood sugar so less insulin is needed).
• Physical exercise makes you more responsive to insulin, which is why it’s such an important part of diabetes control (and overall health!). Don’t put off getting more exercise until you’ve been diagnosed with diabetes. The sooner you act (literally), the better off you will be.
• Losing weight, avoiding high blood sugar, lowering stress, and getting adequate sleep are all crucial (physical exercise might help you get more zzzs).

Gluconeogenesis Disorders

Some of disorder associated with the gluconeogenesis pathway are given below:

• Von Gierke Disease: commonly known as glycogen storage disorder type 1A. Patients with this disorder are unable to convert glycogen into glucose. An insufficient amount of the enzyme glucose-6-phosphatase is the root cause of this disease.
• Hepatomegaly and hypoglycemia: These are common clinical symptoms in newborns, usually between the ages of three and six months (although the age of presentation can vary). An enzyme test and a liver biopsy are used to confirm the diagnosis. To avoid long-term issues, it can be treated with the right nutritional therapy.
• The genetic disorder A mutation in the AGL gene, which on chromosome 1p21 codes for the glycogen debranching enzyme (amylo-1,6-glucosidase), causes Cori disease, also known as glycogen storage disorder type III or limit dextrinosis. The common clinical signs include hypoglycemia, hyperlipidemia, decreased growth, and hepatomegaly.
• McArdle disease: Also known as glycogen storage disorder type V or myophosphorylase deficiency. Glycogen phosphorylase activity is impacted by this disorder. It is an autosomal recessive inborn error of skeletal muscle metabolism that prevents glycogen from being broken down.

Conclusion – Gluconeogenesis

In conclusion, gluconeogenesis is a vital metabolic pathway that allows the body to synthesize glucose from non-carbohydrate sources during periods of fasting or low carbohydrate intake. This process occurs primarily in the liver and kidneys and helps maintain stable blood glucose levels, ensuring energy availability for various tissues and organs. Learning the process of gluconeogenesis is essential for understanding metabolic regulation and addressing conditions like insulin resistance and disorders associated with glucose metabolism.

Also Read:

• Carbohydrate Metabolism
• Krebs Cycle or Citric Acid Cycle
• Glucocorticoid Signaling