Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates.
Gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys.
It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) to maintain blood sugar levels, avoiding low levels of hypoglycemia.
The process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.
Substrates for gluconeogenesis may come from any non-carbohydrate sources that can be converted to pyruvate or intermediates of glycolysis.
For the breakdown of proteins, these substrates include glucogenic amino acids. from breakdown of lipids such as triglycerides, and they include glycerol, odd-chain fatty acids and from other parts of metabolism that includes lactate from the Cori cycle.
Under conditions of prolonged fasting, acetone derived from ketone bodies can also serve as a substrate, providing a pathway from fatty acids to glucose.
Most gluconeogenesis occurs in the liver, and the relative contribution of gluconeogenesis by the kidney is increased in diabetes and prolonged fasting.
Amino acids are classified according to the abilities of their products to enter gluconeogenesis:glucogenic amino acids have this ability, but Ketogenic amino acids do not.
Some amino acids are catabolized into both glucogenic and ketogenic products.
The main gluconeogenic precursors are lactate, glycerol, which is a part of the triglyceride molecule, alanine and glutamine.
They account for over 90% of the overall gluconeogenesis.
Other glucogenic amino acids and all citric acid cycle intermediates can also function as substrates for gluconeogenesis.
Generally, human consumption of gluconeogenic substrates in food does not result in increased gluconeogenesis.
Propionate arises from the β-oxidation of odd-chain and branched-chain fatty acids, and is a minor) substrate for gluconeogenesis.
Lactate is transported back to the liver where it is converted into pyruvate by the Cori cycle using the enzyme lactate dehydrogenase.
Pyruvate, the first designated substrate of the gluconeogenic pathway, can then be used to generate glucose.
The contribution of Cori cycle lactate to overall glucose production increases with fasting duration.
Specifically, after 12, 20, and 40 hours of fasting by human volunteers, the contribution of Cori cycle lactate to gluconeogenesis was 41%, 71%, and 92%, respectively.
Ketone bodies derived from fatty acids could account for up to 11% of gluconeogenesis during starvation.
Catabolism of fatty acids also produces energy in the form of ATP that is necessary for the gluconeogenesis pathway.
Gluconeogenesis has been believed to be restricted to the liver, the kidney, the intestine, and muscle, and evidence indicates gluconeogenesis occurring in astrocytes of the brain.
These organs use somewhat different gluconeogenic precursors: liver preferentially uses lactate, glycerol, and glucogenic amino acids, especially alanine, while the kidney preferentially uses lactate, glutamine and glycerol.
Lactate from the Cori cycle is quantitatively the largest source of substrate for gluconeogenesis, especially for the kidney.
The liver uses both glycogenolysis and gluconeogenesis to produce glucose, whereas the kidney only uses gluconeogenesis.
After eating, the liver shifts to glycogen synthesis, whereas the kidney increases gluconeogenesis.
The intestine uses mostly glutamine and glycerol.
In all species, the formation of oxaloacetate from pyruvate and TCA cycle intermediates is restricted to the mitochondrion, and the enzymes that convert Phosphoenolpyruvic acid (PEP) to glucose-6-phosphate are found in the cytosol.
Transport of PEP across the mitochondrial membrane is accomplished by dedicated transport proteins; however no such proteins exist for oxaloacetate.
Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions.
The pathway begins in either the liver or kidney, in the mitochondria or cytoplasm of those cells, this being dependent on the substrate being used.
Many of the reactions are the reverse of steps found in glycolysis.
Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate by the carboxylation of pyruvate, which reaction also requires one molecule of ATP, and is catalyzed by pyruvate carboxylase.
This enzyme is stimulated by high levels of acetyl-CoA, produced in β-oxidation in the liver, and inhibited by high levels of ADP and glucose.
Glucose is shuttled into the cytoplasm by glucose transporters located in the endoplasmic reticulum’s membrane.
Metabolism of common monosaccharides, including glycolysis, gluconeogenesis, glycogenesis and glycogenolysis
Most steps in gluconeogenesis are the reverse of those found in glycolysis, three regulated and strongly endergonic reactions are replaced with more kinetically favorable reactions.
This system of reciprocal control allow glycolysis and gluconeogenesis to inhibit each other and prevents a futile cycle of synthesizing glucose to only break it down.
The majority of the enzymes responsible for gluconeogenesis are found in the cytosol; the exceptions are mitochondrial pyruvate carboxylase?
The rate of gluconeogenesis is ultimately controlled by the action of a key enzyme, fructose-1,6-bisphosphatase, which is also regulated through signal transduction by cAMP and its phosphorylation.
Control of gluconeogenesis is mediated by glucagon which is released when blood glucose is low.
Its release triggers phosphorylation of enzymes and regulatory proteins by Protein Kinase A (a cyclic AMP regulated kinase) resulting in inhibition of glycolysis and stimulation of gluconeogenesis.
Insulin counteracts glucagon by inhibiting gluconeogenesis.
Type 2 diabetes is marked by excess glucagon and insulin resistance from the body.Insulin can no longer inhibit the gene expression of enzymes such as PEPCK which leads to increased levels of hyperglycemia in the body
The anti-diabetic drug metformin reduces blood glucose primarily through inhibition of gluconeogenesis, overcoming the failure of insulin to inhibit gluconeogenesis due to insulin resistance.
The absence of hepatic glucose production has no major effect on the control of fasting plasma glucose concentration.
Compensatory induction of gluconeogenesis occurs in the kidneys and intestine, driven by glucagon, glucocorticoids, and acidosis.
In the liver, the FOX protein FOXO6 normally promotes gluconeogenesis in the fasted state, but insulin blocks FOXO6 upon feeding.
In a condition of insulin resistance, insulin fails to block FOXO6 resulting in continued gluconeogenesis even upon feeding, resulting in high blood glucose (hyperglycemia),
Insulin resistance is a common feature of metabolic syndrome and type 2 diabetes.
Gluconeogenesis is a target of therapy for type 2 diabetes, such as the antidiabetic drug metformin, which inhibits gluconeogenic glucose formation, and stimulates glucose uptake by cells.
Gluconeogenesis is a metabolic pathway that enables the body to synthesize glucose from non-carbohydrate sources, such as lactate, amino acids, and glycerol, ensuring a continuous supply of glucose especially during fasting, starvation, or periods of low carbohydrate intake.
Gluconeogenesis predominantly occurs in the liver and, to a lesser extent, in the kidneys.
The process involves a series of enzyme-catalyzed reactions that convert substrates like pyruvate, lactate (from the Cori cycle), glucogenic amino acids (like alanine and glutamine), and glycerol (from fat breakdown) into glucose.
Key enzymes include pyruvate carboxylase, phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase, and glucose-6-phosphatase.
Gluconeogebesus helps maintain blood glucose levels between meals and during prolonged fasting, preventing hypoglycemia. Gluconeogenesis is stimulated by hormones like glucagon, cortisol, growth hormone, and epinephrine, while insulin inhibits it
This pathway is especially critical for tissues dependent on glucose, such as the brain, red blood cells, and kidney Gluconeogenesis
Substrates of gluconeogenesus is glutamine, and glycerol.
They process is tightly regulated at multiple levels, including hormonal control, gene expression, and substrate availability
Gluconeogenesis is essential for glucose homeostasis when dietary carbohydrate is insufficient or unavailable.