The gluconeogenesis pathway seems quite pointless to me. I don't understand why an organism would want to spend energy to create a molecule that can then be metabolized again for less energy? The pathway seems only to serve as a complete waste of energy?

Can someone explain why we have gluconeogenesis and when it is used?


Gluconeogenesis is not the reversal of the glycolysis, but the generation of glucose from non-carbohydrate precursors (like odd chain fatty acids and proteins). The reason why we have this process is because some organs and tissues can only use glucose as their energy source. These include the brain (although ketone bodies can be used here as well), erythrocytes, testes and the kidney medulla.

Usually the glucose for the supply of these tissues comes directly from carbohydrates in food or storage carbohydrates as glycogen or starch, but when these are not available, the body has another way to get around this problem and to avoid the starvation of these tissues. See for example here and here.

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    $\begingroup$ fatty acids are not a substrate for gluconeogenesis. $\endgroup$ – AliceD Apr 8 '15 at 1:33
  • $\begingroup$ @AliceD Fatty acids are no direct source for gluconeogenesis, but where does the necessary Acetyl-CoA come from? For example from the beta-oxidation of fatty acids. $\endgroup$ – Chris Apr 8 '15 at 5:32
  • $\begingroup$ I thought the backbone of the glucose as the end product is not structurally related to fatty acids, but to the substrate of GNG such as amino acids. As the answer is formulated it reads like fatty acids are converted to glucose, which is not the case. I thought an essential feature of metabolism in general was that sugars can be converted to fatty acids, but not the reverse. Hence the problems people have to reduce bodily fat. GNG doesn't take fatty acids in as a substrate. Correct me if I am wrong. $\endgroup$ – AliceD Apr 8 '15 at 5:56
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    $\begingroup$ I will make the answer clearer later today. $\endgroup$ – Chris Apr 8 '15 at 6:21
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    $\begingroup$ @AliceD In a way, we are both right. Odd chain fatty acids can be oxidized to propionyl-CoA which is then converted into succinyl-CoA and further into pyruvate, which can enter the glucneogenesis pathway. Even chain fatty acids are oxidized to Acetyl-CoA which enters the TCA cycle but cannot be used for making glucose. It's good to have the thick biochemistry books at hand :-) $\endgroup$ – Chris Apr 8 '15 at 10:41

Before discussing gluconeogenesis it is necessary to be clear on the following:

  • What organism you are considering
  • Under what physiological circumstances gluconeogenesis is occurring
  • What is the substrate for gluconeogenesis

and, if one is considering mammals:

  • Which tissue is performing the gluconeogenesis
  • Which tissue(s) will consume the glucose produced

because these latter two are never the same,

or in other organisms:

  • What is the glucose produced actually used for


Gluconeogenesis is performed almost exclusively by the liver, which is able to provide the NADH and ATP for this process from its oxidative metabolism. (The kidney also has a small capacity for gluconeogenesis, but the reason for this is another question). The tissues consuming the glucose are predominantly erythrocytes, brain and nervous tissue and muscle, depending on the circumstances.

Resting post-absorptive ‘lactate recycling’

Erythrocytes have no mitochondria so can only respire by anaerobic glycolysis, reducing the pyruvate to lactate (in order to regenerate NAD+). The lactate goes into the blood, and is taken up by the liver and oxidized to pyruvate. Gluconeogenesis converts the pyruvate to glucose which passes back into the bloodstream, restoring that used by the erythrocytes. (The brain also uses glucose here but I’ll deal with it below.)

‘Lactate recycling’ in exercise

Muscle has a certain aerobic capacity depending on type. However in vigorous exercise the skeletal muscle becomes anaerobic and obtains ATP for muscle contraction from aerobic glycolysis, again producing lactate. The liver glycolysis recycles this lactate to maintain the blood glucose, as in the previous section. (This overall co-ordination between tissues is often called ‘Cori Cycle’ in text books. However the name can be misleading, as it is not a chemical cycle like the tricarboxylic acid cycle or the urea cycle.)


In starvation the net supplies of energy will fall. However the one tissue that must be kept supplied with a glucose is the brain (even though it can obtain part of its energy requirements from other sources). Liver gluconeogenesis provides this, but substrates other than lactate are need to restore the glucose lost by net consumption after the liver glycogen reserves have been depleted. The main gluconeogenic precursors are a subset of amino acids from protein breakdown (the so-called glucogenic amino acids) which feed in at different parts of the pathway. Glycerol from the breakdown of triglycerides can also be used, but fatty acids themselves cannot, because they are converted to acetyl CoA, which condenses with oxaloacetate to feed into the tricarboxylic acid cycle, and produces no net carbon skeleton that could be used for glycolysis.


I am not a plant biochemist, so I am happy to be corrected if wrong, but I understand that gluconeogenesis is important after seed germination for production of hexoses for use in cell wall polysaccharides during growth. Seeds contain reserves of fat, which on germination is oxidized to acetyl CoA which passes into the tricarboxylic acid cycle. However plants (and some bacteria) are able to convert this to pyruvate by means of a pathway mammals lack — the glyoxylate cycle (http://www.ncbi.nlm.nih.gov/books/NBK22383/). So in plants the glucose produced is not being used to provide energy by oxidation, but as a biosynthetic precursor.


Gluconeogenesis is present in certain bacteria, where the pathway presumably arose (rather than in mammals). So it is of interest to consider its role there. Again, I am no bacteriologist, but the glyoxylate cycle is also present in bacteria, and it is likely that one function of gluconeogenesis would be to allow growth on fatty acids, with the glucose produced being required for synthesis of cell-wall polysaccharides.

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Gluconeogenesis occurs during prolonged starvation or overnight fasting, mostly in liver and kidney to provide glucose to brain and RBCs. As brain and red blood cells require continuous glucose for their activity, this process comes in handy. The steps involved in gluconeogenesis are different from that of glycolysis, it is not the reverse of it. You can get more details 1 and 2.

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    $\begingroup$ Could you expand on the linked articles please? I also don't think this answers the question $\endgroup$ – rg255 Mar 13 '16 at 8:31

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