Gluconeogenesis is a term that describes the synthesis of glucose from endogenous noncarbohydrate substrates.

  1. The physiological function of gluconeogenesis
  2. Gluconeogenesis vs glycolysis - key enzymes
  3. Gluconeogenic precursors

Primary gluconeogenic precursors are lactate, glycerol, and the carbon skeletons of the amino acids - alanine and glutamine.

The physiological function of gluconeogenesis and conditions that activate it

Some tissues, particularly the brain, red blood cells, and the renal medulla, depend heavily on glycolysis to satisfy their ATP (adenosine triphosphate) needs.

The gluconeogenesis pathway is essential for maintaining the concentration of blood glucose within its normal physiological ranges.

The glycogen stores of the body are limited and provide only about an 8 – to an l0-hour supply of glucose.

There are 2 main physiological conditions when gluconeogenesis is active:

  1. in the fasted state;
  2. during intense exercise.

Maintaining of blood sugar level during fasting

In the fasted state, when dietary carbohydrates have been utilized or stored as glycogen, and the plasma concentration of glucose has declined, the liver starts synthesizing glucose in response to the decreased insulin/glucagon ratio. It occurs after postprandial processing of absorbed nutrients.

The liver increases the rate of gluconeogenesis as glycogen stores become depleted during a subsequent fasting period.

Physical exercise and blood glucose level

During prolonged physical exercise gluconeogenesis also increases and serves to provide glucose for heart and active skeletal muscle.

After exercise, the rate of gluconeogenesis remains elevated and contributes to modest replenishment of muscle glycogen stores prior to the availability of dietary glucose.

During both fasting and recovery from prolonged exercise, the substantial energy cost of gluconeogenesis is met primarily by concurrent b-oxidation of fatty acids to acetyl-CoA in the liver.

Gluconeogenesis vs glycolysis - key enzymes

Gluconeogenesis steps

gluconeogenesis steps

The pathway for gluconeogenesis utilizes many, but not all, of the enzymes of glycolysis.

The reactions that are common to glycolysis and gluconeogenesis are the reversible reactions.

Three irreversible steps from the glycolytic pathway must be by-passed during the synthesis of new glucose from pyruvate (or lactate).

Two of these irreversible steps are the two ATP-requiring activation reactions of glycolysis catalyzed by glucokinase and phosphofructokinase-1. They are bypassed by glucose 6-phosphatase and fructose 1,6-bisphosphatase, respectively.

The third irreversible step of glycolysis is the second ATP-generating reaction, which is catalyzed by pyruvate kinase.

The gluconeogenesis pathway utilizes the reactions catalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxykinase to bypass the irreversible pyruvate kinase reaction of glycolysis.

Video - Gluconeogenesis - Biochemistry


Gluconeogenic precursors

Substrates of gluconeogenesis are:

  1. lactate;
  2. glucogenic amino acids;
  3. glycerol;
  4. odd-chain fatty acids.

The Cori cycle - lactate to glucose pathway

Lactate is the endpoint of glycolysis when pyruvate cannot be metabolized through pyruvate dehydrogenase and the TCA (tricarboxylic acid cycle) cycle.

Anaerobic glycolysis occurs in red blood cells, in the renal medulla, and in skeletal muscle during strenuous exercise.

Gluconeogenesis provides a mechanism by which the liver and renal cortex can regenerate glucose from lactate, thereby ensuring a constant supply of glucose for those cells and tissues that are highly dependent on glycolysis for their energy needs.

The Cori cycle is the metabolic interchange between lactate-generating cells and gluconeogenic cells.

The Cori cycle

The Cori cycleMore energy is required to generate glucose from lactate in the liver than is obtained by oxidizing glucose in red blood cells.

Gluconeogenesis from lactate requires 6 ATP equivalents (4 ATP, 2 GTP) to produce one molecule of glucose.

Glycolysis of glucose to lactate produces a net of two molecules of ATP per molecule of glucose oxidized.

It may appear that continued breakdown and resynthesis of glucose is wasteful. It is, however, the small energy cost paid by the liver and renal cortex to permit effective functioning of other cells.

Lactate  to Pyruvate conversion

Erythrocytes completely dependent on glycolysis to lactate for their ATP. Glycolysis to lactate is also advantageous during strenuous exercise.

Although the yield of ATP per glucose molecule metabolized is much lower than when glucose is oxidized all the way to CO2 and water, the rate at which ATP can be generated by glycolysis is greater than the rate at which ATP can be produced by oxidative phosphorylation.

The conversion of lactate to glucose occurs in the liver, where ample ATP can be generated from the b-oxidation of long-chain fatty acids.

Video - Cori Cycle: Lactate Recycling

Glucogenic amino acids

Main glucogenic amino acids are alanine and glutamine.

Alanine cycle

Alanine is the major gluconeogenic amino acid substrate of the liver.

In the fasted state, proteolysis of muscle proteins provides substrates for maintaining blood glucose homeostasis.

However, not all amino acid carbon skeletons can be converted into glucose.

In particular, muscle protein contains a significant percentage (approximately 20 percent) of branched-chain amino acids that are ketogenic or mixed ketogenic and glucogenic.

Oxidation of the carbon chains of branched-chain amino acids occurs primarily within muscles and serves as a significant energy source for muscle during fasting.

Before branched-chain amino acids can be oxidized, the a-amino groups must be removed by transamination and exported from the muscle primarily as alanine and glutamine.

Conversion of alanine to pyruvate

In the synthesis of alanine in muscle, pyruvate serves as the acceptor molecule for the a-amino groups transferred, with the pyruvate being derived from glycolysis. This means that muscle cells need a constant supply of glucose to sustain the net export of gluconeogenic precursors. That glucose supply is provided mainly by hepatic gluconeogenesis from alanine.

The alanine cycle is the interorgan cycle of glucose catabolism in the muscle to generate alanine and the recycling of the carbon skeletons of alanine to glucose in the liver.

Like the Cori cycle, the alanine cycle has a net energy cost.

Nevertheless, the alanine cycle has significant advantages to the organism as a whole since it permits efficient catabolism of muscle proteins that provide substrates for gluconeogenesis.

The alanine cycle

Glucose alanine cycle

The pathway for hepatic gluconeogenesis from alanine is similar to that from lactate in that both lactate and alanine are readily converted to pyruvate. In the case of alanine, the reaction involves transamination in which the a-amino group of an amino acid is transferred to a-ketoglutarate and subsequently excreted as urea.

Video - Glucose-alanine cycle

Renal gluconeogenesis of glutamine

Glutamine is the preferred substrate for gluconeogenesis in the renal cortex.

Like alanine, glutamine is synthesized by skeletal muscle in the fasted state as a means of exporting the amino groups of amino acids.

In the kidney, the two amino groups of glutamine are removed producing free ammonium ions and a-ketoglutarate.

The ammonium ions serve to buffer acids excreted in the urine, while the a-ketoglutarate provides the substrate for gluconeogenesis.

As a result of the linkage between the generation of free ammonium ions and a-ketoglutarate, gluconeogenesis in the kidney increases significantly during conditions of acidosis as well as fasting.

Oxidation of a-ketoglutarate via the TCA (tricarboxylic acid cycle) cycle produces oxaloacetate, which then enters the same pathway as that used to synthesize glucose from lactate.

Conversion of glucogenic amino acids to glucose

A number of the other amino acids can contribute all or a part of their carbon skeletons to gluconeogenesis.

In each instance, the carbon skeletons of these glucogenic amino acids are metabolized either to pyruvate or to one of the TCA-cycle intermediates, such as oxaloacetate, succinyl-CoA, or a-ketoglutarate.

Glucogenic and ketogenic amino acids

Glucogenic and ketogenic amino acids and gluconeogenesis

Amino acids that generate:

  • pyruvate: alanine, cysteine, glycine, methionine, serine, threonine, and tryptophan.
  • a-ketoglutarate: arginine, glutamate, glutamine, histidine, and proline.
  • succinyl-CoA: isoleucine, threonine, and valine.
  • fumarate: phenylalanine, tyrosine, and aspartate (via the urea cycle).
  • oxaloacetate: asparagine and aspartate.

Glycerol to glucose conversion

In the fasted state, mobilization of adipose triacylglycerols provides free fatty acids and glycerol.

Although even-chain fatty acids are catabolized to acetyl-CoA and, like ketogenic amino acids, are not substrates for gluconeogenesis, the glycerol that is released during lipolysis can be a significant source of substrate for glucose synthesis.

Glycerol in gluconeogenesis

Gluconeogenesis of fatty acids

Unlike such fuel sources such as amino acids, lactate, and glycerol, the carbon skeletons of most fatty acids cannot be utilized for gluconeogenesis.

Almost all physiological fatty acids contain even numbers of carbons (usually, C16 or C18) and their catabolism involves cleavage of the fatty acid chain into two-carbon acetyl-CoA units.

Even chain fatty acids cannot be used to make glucose because humans and other animals lack a pathway for converting acetyl-CoA to glucose.

On the other hand, the oxidation of the relatively rare odd-chain fatty acids and branched methyl fatty acids that are present in human diets do generate small amounts of propionic acid that can be converted into glucose.

Gluconeogenesis - Allosteric Regulation