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The major substrates of gluconeogenesis are-

1) Lactate

2) Glycerol

3) Propionate

4) Glucogenic amino acids

The entry of non carbohydrate precursors into the pathway of glucose production is as follows-

1) Lactate– Lactate is a major source of carbon atoms for glucose synthesis by gluconeogenesis. It is formed by active skeletal muscle when the rate of glycolysis exceeds the rate of oxidative metabolism. It is also the end product of glycolysis in red blood cells and in the cells deprived of mitochondria. Lactate is readily converted into pyruvate by the action of lactate dehydrogenase (Figure-1).

 Lactate to pyruvate conversion

Figure-1- Reversible Lactate to pyruvate conversion depends upon the availability of NAD+ or NADH

Biological significance

This reaction serves two critical functions during anaerobic glycolysis.

1) First, in the direction of lactate formation the LDH reaction requires NADH and yields NAD+ which is then available for use by the glyceraldehyde-3-phosphate dehydrogenase reaction of glycolysis. These two reactions are, therefore, intimately coupled during anaerobic glycolysis.

 Lactic acid fermentation

Figure-2- The coupling of reactions catalyzed by Glyceraldehyde-3-Phosphate dehydrogenase and Lactate dehydrogenase allows the glycolysis to continue making the constant availability of NAD

2) Cori’s cycle- The lactate produced by the LDH reaction is released into the blood stream and transported to the liver where it is converted to glucose. The glucose is then returned to the blood for use by muscle as an energy source and to replenish glycogen stores. This cycle is termed the Cori cycle (Figure-3).

Corri cycle

Figure-3- Liver furnishes glucose to contracting skeletal muscle, which derives ATP from the glycolytic conversion of glucose into lactate. Contracting skeletal muscle supplies lactate to the liver, which uses it to synthesize glucose.

2) Glycerol-The hydrolysis of triacylglycerols in fat cells yield glycerol and fatty acids. Glycerol may enter either the gluconeogenic or the glycolytic pathway at Dihydroxyacetone phosphate;however, the carbons of the fatty acids cannot be utilized for net synthesis of glucose (see details below).In the fasting state glycerol released from lipolysis of adipose tissue triacylglycerol is used solely as a substrate for gluconeogenesis in the liver and kidneys. This requires phosphorylation to glycerol-3-phosphate by glycerol kinase and dehydrogenation to Dihydroxyacetone phosphate (DHAP) by glyceraldehyde-3-phosphate dehydrogenase (G3PDH) (Figure-4).


 Glycerol activation

Figure-4- Activation of glycerol is needed for subsequent esterification to form triglycerides.

Glycerol kinase is absent in adipose tissue, glycerol released by hydrolysis of triglycerides  cannot be utilized for reesterificaton,  hence it is a waste product, It is carried through circulation to the liver and is used for gluconeogenesis or glycolysis as the need may be.In fact adipocytes require a basal level of glycolysis in order to provide them with DHAP as an intermediate in the synthesis of triacylglycerols.

Gluconeogenesis requires a coordinated supply of precursors from muscle and adipose tissue to the liver (and kidneys). Muscle provides lactate, pyruvate, Alanine, glutamine, and other amino acids. Triglycerides in adipose tissue are broken down into fatty acids and glycerol, which is a gluconeogenic precursor. Fatty acids provide an alternative oxidative fuel to tissues other than the brain (which requires glucose).

3) Propionate– Propionate is a major precursor of glucose in ruminants; it enters gluconeogenesis via the citric acid cycle. In non-ruminants, including humans, propionate arises from the Beta -oxidation of odd-chain fatty acids that occur in ruminant lipids, as well as the oxidation of isoleucine and the side-chain of cholesterol, and is a (relatively minor) substrate for gluconeogenesis (Figure-5)

 Fate of propionate

Figure- 5- After esterification with CoA, Propionyl-CoA is carboxylated to D-Methylmalonyl-CoA, catalyzed by Propionyl-CoA carboxylase, a biotin-dependent enzyme. Methylmalonyl-CoA racemase catalyzes the conversion of D-Methylmalonyl-CoA to L-Methylmalonyl-CoA, which then undergoes isomerization to succinyl-CoA catalyzed by Methylmalonyl-CoA mutase.

Methylmalonyl CoA Isomerase/ mutase is a vitamin B12 dependent enzyme, and in deficiency methylmalonic acid is excreted in the urine (methylmalonic aciduria).

Role of fatty acids in glucose production-

Even chain fatty acids are not the glucogenic precursors, Oxidation of these fatty acids yields enormous amounts of energy on a molar basis, however, the carbons of the fatty acids cannot be utilized for the net synthesis of glucose. The two carbon unit of acetyl-CoA derived from β-oxidation of fatty acids can be incorporated into the TCA cycle, however, during the TCA cycle two carbons are lost as CO2. Moreover the formation of acetyl CoA from pyruvate is an irreversible step, thus acetyl CoA cannot be converted back into glucose. The oxidative decarboxylation of pyruvate to acetyl CoA commits the carbon atoms of glucose to two principal fates: oxidation to CO2 by the citric acid cycle, with the concomitant generation of energy, or incorporation into lipid (Figure-6),  Thus, explaining why even chain fatty acids do not undergo a net conversion of carbohydrate.

Odd chain fatty acids on oxidation produce Propionyl Co A which is a substrate for gluconeogenesis through the formation of succinyl Co A.

Glycerol component of fats can also be utilized for the formation of glucose through the formation of dihydroxy acetone phosphate. Hence, therefore except for even chain fatty acids, the other fat components are glucogenic, so the statement that “It is incorrect to say that fats cannot be converted to glucose”, is a justified statement.


 Conversion of glucose to fats

Figure- 6- Glucose can be converted to Fatty acids, but due to irreversible reaction of conversion of pyruvate to acetyl Co A and the loss of both the carbons of acetyl Co A in TCA cycle as CO2, even chain fatty acids that yield Acetyl Co A upon oxidation cannot be considered glucogenic.

Summary (Figure-7)

1) Lactate enters as pyruvate

2) Glycerol enters as Dihydroxy acetone phosphate

3) Propionate enters as Succinyl Co A

4) Glucogenic amino acids (To be covered in the next post)


 Barriers of gluconeogenesis


Figure -7- steps of gluconeogenesis and entry of various non carbohydrate precursors into the main pathway for glucose production

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