# Cori Cycle
Category: Metabolism
Also known as: lactate shuttle
The Cori cycle is a metabolic loop in which lactate, produced by tissues engaged in aerobic glycolysis, is transported to the liver and reconverted into glucose. Peat framed this cycle not as a benign shuttle but as a pathological drain, noting that when lactate is carried to…
11 passages · 3 authors · 1997–2022 · Most-cited: [Ray Peat](https://bioenergeticoracle.com/md/voices/ray-peat/index.md)
Canonical page: https://bioenergeticoracle.com/concepts/cori-cycle
## Synthesis
**The Cori cycle** is a metabolic loop in which **lactate**, produced by tissues engaged in *aerobic glycolysis*, is transported to the liver and reconverted into glucose. [Source 1, 2] Peat framed this cycle not as a benign shuttle but as a pathological drain, noting that when lactate is carried to the liver, its conversion to glucose adds to the energy drain on the organism. [Source 4] Dinkov has described the subjective experience of this cycle as a systemic "downing effect," where the constant interconversion of pyruvate and lactate creates a *vicious cycle* of inefficient energy production that leaves a person feeling heavy and lethargic. [Source 2]
The cycle is driven by a respiratory defect in which cells fail to oxidize glucose completely to carbon dioxide, even in the presence of oxygen. [Source 1] Peat argued that the relevant therapeutic intervention is the prevention of lactate formation—or the stimulation of its oxidation—to prevent its entry into the Cori cycle for gluconeogenesis. [Source 1] He identified **thyroid hormone**, **magnesium**, and **progesterone** as key factors that make respiration efficient, producing sufficient ATP to trigger the Pasteur effect and shut down glycolysis, thereby stopping the flow of substrate into the cycle. [Source 1] The carbon dioxide produced by efficient oxidation is itself a crucial antagonist, as Peat explained the "lactate paradox" of high altitude by noting that retained **CO2** takes care of the lactic acid, creating a greased pathway for electrons that prevents the reductive stress that forms lactate. [Source 5, 9]
Peat treated the Cori cycle as a central mechanism of systemic degeneration because the lactate that fuels it is not merely a marker of stress but a direct contributor to tissue damage. [Source 3, 10] He documented that lactate increases blood viscosity, mimics stress, causes inflammation, and promotes the growth of new blood vessels, thereby supporting tumor expansion. [Source 3, 10] In the brain, lactate accumulation causes nerve cell loss by increasing the release of *excitotoxic glutamate*, and a panic reaction produced by sodium lactate reduces protective neurosteroids, making the brain more susceptible to damage. [Source 3] Roddy has connected this to a hormonal cascade in which injected lactate increases **prolactin**, which in turn suppresses thyroid function, locking the organism into a self-reinforcing loop of stress and inefficient energy production. [Source 11]
The cycle also intersects with the **Randle cycle**, where the oxidation of fatty acids suppresses glucose oxidation, reducing CO2 and shunting pyruvate toward lactate. [Source 6, 7] Peat observed that cancer cells exploit this dynamic, turning glucose into lactate or fat and then oxidizing the fat, a process that does not produce as much carbon dioxide and leads the cell down a path of reduced function. [Source 7] The healthy brain, in contrast, uses a localized version of this cycle adaptively; astrocytes can absorb lactate from excited neurons and convert it back to glucose via gluconeogenesis, storing it as glycogen during rest. [Source 8] However, Peat warned that lactate revisionists who concentrate on this utility distract attention from the effects of increasing lactate in the systemic circulation on brain metabolism. [Source 8]
## People also ask
### How does the Cori cycle drain energy instead of producing it?
Peat argued that when the liver converts lactate back into glucose, this process adds to the organism's overall energy drain, creating a vicious cycle of inefficient energy production that Dinkov described as a systemic "downing effect" leaving a person feeling heavy and lethargic.
### What substances did Peat recommend to stop the Cori cycle?
Peat identified thyroid hormone, magnesium, and progesterone as key factors that make respiration efficient, producing enough ATP to trigger the Pasteur effect and shut down glycolysis, thereby preventing the lactate formation that feeds the cycle.
### How does the Cori cycle relate to the Randle cycle?
The entry describes that in the Randle cycle, fatty acid oxidation suppresses glucose oxidation, which reduces carbon dioxide and shunts pyruvate toward lactate, thereby providing more substrate for the Cori cycle.
## Related concepts
- [Lactate paradox](https://bioenergeticoracle.com/md/concepts/lactate-paradox/index.md)
- [Bohr effect](https://bioenergeticoracle.com/md/concepts/bohr-effect/index.md)
- [Cancer](https://bioenergeticoracle.com/md/concepts/cancer/index.md)
- [Endometriosis](https://bioenergeticoracle.com/md/concepts/endometriosis/index.md)
- [Estrogen dominance](https://bioenergeticoracle.com/md/concepts/estrogen-dominance/index.md)
- [Albumin](https://bioenergeticoracle.com/md/concepts/albumin/index.md)
## Cited passages
Passage numbers match the `[Source N]` markers in the synthesis above.
### Source 1 — From PMS to Menopause: Female Hormones in Context
Ray Peat · Book · 1997
> **Ray Peat:** The relevant effects of thyroid (especially with progesterone, to promote tissue response to thyroid, to block cortisol production, and to provide general anti-stress physiological support) however, are stimulation of protein synthesis and the prevention of lactate formation--or the stimulation of its oxidation, either by the tumor itself or by other tissues, to prevent its entry into the Cori cycle, for gluconeogenesis. Cachexia strumipriva, the wasting disease that used to result following removal of the thyroid gland when the thyroid hormone wasn't replaced, should be kept in mind, since it is a situation in which thyroid cures cachexia, stimulating anabolic processes. There has been publicity in recent decades about various substances produced by cancers that induce the growth of blood vessels, providing the tumors with the circulation needed for growth. Since lactic acid is an adequate stimulus for such growth, and is produced by tumors, it is remarkable that it has been so consistently ignored as a reasonable point of intervention for limiting tumor growth. Thyroid and magnesium make respiration efficient, in the sense of producing ATP, which is required for the Pasteur effect to turn off glycolysis. Lactic acid can't be made (in humans) from fats or alcohol, a point which is often overlooked by biochemists who work with bacteria, and so the use of acetic acid, butyric acid, and other fatty acids (as in coconut oil, for example), combined with adequate thyroid hormone and magnesium, should make a significant contribution toward removing the lactate stimulus for increased blood supply to the tumor. The carbon dioxide produced by the action of thyroid is itself involved in the suppression of lactic acid formation. Progesterone and pregnenolone, by reducing the cancer-induced excess of the glucocorticoid hormones, would also make a contribution to decreasing the supply of glucose to the tumor.
### Source 2 — Exhausted? Tired all the Time? Low Energy? Chronic Fatigue - Georgi Dinkov
Georgi Dinkov · Interview · Jun 30, 2019 · https://www.youtube.com/watch?v=FdLJakdEhZs
> **Georgi Dinkov:** And the way this happens is lactic acid is transported from various tissues back to the liver, where for something called the Cori cycle, it gets converted back into pyruvate. But you see the vicious cycle here. If pyruvate cannot continue on, through the various steps various jumps of the metabolic pathway and it cannot properly get to oxygen to create the carbon dioxide and water as the final byproduct which is going to keep cycling through this pyruvate lactate pyruvate lactate pyruvate lactate cycle and it's a very inefficient way of producing energy And even if it was working well, still the very fact that we're overproducing lactate has a very systemic sort of like downing effect on us, both on mood and on physiological functioning, which most people, you know, tend to feel as, ah. i'm always like you know it's almost like i'm dragging myself with this tremendous effort like my legs like don't want to move you know they just they're kind of like stuck to the ground and i have to drag my feet almost with with this mental exertion i have to force myself to move all of this is kind of like the result of of inefficient energy production high lactate high cortisol high serotonin etc etc and opposite to that is you know most people during the summer especially when they're feeling healthier they feel very light on their feet that expression comes from somewhere you feel like when you feed that's where it's coming from it's it comes from an abundance of energy and you can actually the reason um you know most people feel frolicking and playful when they have it when they have this you know during the summers because they have extra energy like if you don't have energy to spend clearly in the winter when you're barely moving You're not going to feel like playing racquetball or softball or football, whatever it is. You can barely move, right?
### Source 3 — Lactate vs. CO2 in Wounds, Sickness, and Aging
Ray Peat · Newsletter · Aug 3, 2009
> [[52](#ref052)]
>
> Nervous and hormonal factors can cause lactate to accumulate, even without prior damage to the mitochondria.[[37](#ref037)] Psychological, as well as physical, stress and overactivation of glutamate receptors can cause harmful accumulation of lactate in the brain.[[58](#ref058)] Rather than just being “associated with” tissue damage, lactate directly contributes to the damage, for example in the brain, causing nerve cell loss by increasing the release of excitotoxic glutamate.[[62](#ref062)] When a panic reaction is produced by sodium lactate, the reduction of protective neurosteroids appears to contribute to the excitatory state;[[18](#ref018)] this would make the brain more susceptible to damage.
>
> Lactate increases blood viscosity, mimics stress, causes inflammation, and contributes to shock. Lactated Ringer's solution contributes to the tissue damage caused by shock, when it's used to resuscitate shock victims:[[15](#ref015), [17](#ref017)] it contributes to the inflammatory processes associated with shock, unlike the use of hypertonic saline and other solutions. Lactate contributes to diabetes, inhibiting the ability to oxidize glucose. It promotes endothelial cell migration and leakiness, with increased vascular permeability factor (VPF or vascular endothelial growth factor, VEGF):[[46](#ref046)] this can lead to breakdown of the “blood-brain barrier.”
>
> In the brain, lactate can cause nerve damage, increasing intracellular fat accumulation, chromatin clumping, and mitochondrial swelling.[[49](#ref049)]
>
> The lactate in peritoneal dialysis solution impairs differentiation and maturation of (immune, monocyte derived) dendritic cells; according to the authors of the study, “These findings have important implications for the initiation of immune responses under high lactate conditions, such as those occurring within tumor tissues or after macrophage activation.”[[51](#ref051)]
>
> Lactate also causes macrophages and synovial fibroblasts to release PGE 2, which can contribute to inflammation and bone resorption.[[13](#ref013)] This is the prostaglandin known to activate the formation of estrogen.
### Source 4 — Lactate vs. CO2 in Wounds, Sickness, and Aging
Ray Peat · Newsletter · Aug 3, 2009
> Lactate formation from glucose is increased when anything interferes with respiratory energy production, but lactate, through a variety of mechanisms, can itself suppress cellular respiration. (This has been called the Crabtree effect.) Lactate can also inhibit its own formation, slowing glycolysis. In the healthy cell, the mitochondrion keeps glycolysis working by consuming pyruvate and electrons (or “hydrogens”) from NADH, keeping the cell highly oxidized, with a ratio of NAD +/NADH of about 200. When the mitochondrion's ability to consume pyruvate and NADH is limited, the pyruvate itself accepts the hydrogen from NADH, forming lactic acid and NAD + in the process. As long as lactate leaves the cell as fast as it forms, glycolysis will provide ATP to allow the cell to survive. Oxygen and pyruvate are normally “electron sinks,” regenerating the NAD + needed to produce energy from glucose.
>
> But if too much lactate is present, slowing glycolytic production of ATP, the cell with defective respiration will die unless an alternative electron sink is available. The synthesis of fatty acids is such a sink, if electrons (hydrogens) can be transferred from NADH to NADP +, forming NADPH, which is the reducing substance required for turning carbohydrates and pyruvate and amino acids into fats.
>
> This transfer can be activated by the transhydrogenase enzymes in the mitochondria, and also by interactions of some dehydrogenase enzymes.
>
> The enzyme, fatty acid synthase (FAS), normally active in the liver and fat cells and in the estrogen-stimulated uterus, is highly active in cancers, and its activity is an inverse indicator of prognosis. Inhibiting it can cause cancer cells to die, so the pharmaceutical industry is looking for drugs that can safely inhibit it. This enzyme is closely associated with the rate of cell proliferation, and its activity is increased by both cortisol and estrogen.
>
> The first biochemical event when a cell responds to estrogen is the synthesis of fat. Estrogen can activate transhydrogenases, and early studies of estrogen's biological effects provided considerable evidence that its actions were the result of the steroid molecule's direct participation in hydrogen transfers, oxidations and reductions. E.V.
### Source 5 — Ask the Herb Doctor: Altitude (July 2013)
Ray Peat · Interview · 2013
> **Ray Peat:** The conventional physiologists for years have noticed what they call the ‘lactate paradox’ which is that you can work full force at a high altitude without producing lactic acid; and it’s not really a paradox. It’s that the oxygen is not at a high enough concentration to displace CO2 so the CO2 is taking care of the lactic acid.
>
> **Sarah Johannesen Murray and Andrew Murray:** OK, so in increased CO2 states, oxygen is utilized way more efficiently and way less of it, if any of it, is actually available to react in a free radical formation.
>
> **Ray Peat:** Yeah, it works; one of the ways is that carbo-amino effect simply protecting any amino group from attack by oxygen.
>
> **Sarah Johannesen Murray and Andrew Murray:** But these are on proteins?
>
> **Ray Peat:** Yeah, but it also simply activates the enzymes that direct the electrons to move from glucose or fat down to oxygen. It creates a sort of a greased pathway for the electrons’ movement, and if you block the CO2, or oxygen, the NAD reflects the increased access to electrons, and those electrons tend to diffuse out through the cells causing attack of polyunsaturated fats and genetic material and so on.
### Source 6 — Carcinogenic Metabolism
Ray Peat · Newsletter · 2022
> The depletion of energy by excessive stimulation can lead to a self-maintaining vicious circle, in which fatigue and energy depletion interfere with rest and restoration. Nitric oxide, formed as a result of energy deprivation (Cardenas, et al., 2000), and heme oxygenase, caused by glucose deprivation (Chang, et al., 2002), are major factors in the development of cancer.
>
> Cancer’s outstanding feature is its inability to turn itself off. In the 19th century, Pasteur recognized a regulatory process in yeast, in which the presence of oxygen stopped the fermentative process. Otto Warburg, c. 1923, observed that this process which occurs in normal animal tissues, is absent in all kinds of cancer. He observed that the cancer continues to consume oxygen, but that there is some defect in the process, keeping it from suppressing the formation of lactic acid. Warburg observed that cancers are hypoglycemic, because their rapid conversion of glucose to lactate exceeds the ability of blood vessels to deliver glucose, and that they are hypoxic or anoxic, for the same reason—their consumption of oxygen exceeds the capacity of the blood supply. He demonstrated that prolonged oxygen deprivation could cause normal cells to become cancerous.
>
> The implication of his work is that cancer stimulates its own growth, and that the inflammation-promoting effects of lactate are crucial for its development and properties, and its destructive effects on the host organism. Considering that lactate suppresses immunity, stimulates the formation of new blood vessels and promotes metastasis, the Warburg effect gives an accurate picture of the physiological and environmental nature of cancer. However, it’s important to consider how their other regulatory processes throughout the organism are affected by lactate, in ways that can support the development of cancer, because they provide many opportunities for intervening to slow or reverse the process of cancerization.
>
> Lactate is an activator of growth hormone and heme oxygenase and tends to increase glutamate and cellular excitation and inflammation, while reducing CO2 formation. Glutamate increases growth hormone (Luger, et al., 1992), which promotes oxidation of fatty acids, and reduces oxidation of glucose; the resulting decrease in CO2 leads to increased production of lactate. Dietary fat, like free fatty acids from lipolysis, increases glutamate and lowers the oxidation of glucose (the “Randle cycle”).
### Source 7 — EastWest Healing: Energy and Metabolism
Ray Peat · Interview · Jul 17, 2013 · https://www.youtube.com/watch?v=VaF26fTAkWw
> ## Energy Metabolism and the Randall Cycle
>
> **Ray Peat:** So this whole idea that transporting glucose into the cell is the failure in heart disease or diabetes just isn't the case. If you're making lactic acid, the sugar is getting into the cell. Something goes wrong in the oxidation process and the cell begins to favor the oxidation of fat rather than glucose. That doesn't produce as much carbon dioxide, and that seems to be a basic problem for the cell that leads it down the path of reduced function and eventual non-survival. A very similar thing happens in cancer cells. They begin turning glucose into lactic acid or fat, and then they oxidize the fat. In treating heart disease over the last five years, there's been a movement towards thinking of ways to stop the oxidation of fatty acids, allowing the heart to avoid the Randall Cycle and get back to oxidizing glucose instead of turning it into lactic acid.
### Source 8 — Lactate, metabolic regression, & political-medical implications
Ray Peat · Newsletter · 2020
> A few people have kept arguing for that hypothesis, at the same time that others are arguing that lactate isn’t essential for cancer, or that it’s anti-inflammatory, or that it’s essential for immunity, or for healing an injured brain, etc. Added to the historical antagonism of the pharmaceutical-medical industry to Warburg’s discoveries, this new wave of publications is intensifying the confusion about lactate’s functions.
>
> If it’s recognized that the ratio of lactate to pyruvate in the body fluids affects the redox balance of every cell in the body, and that this balance affects in a highly systematic way the metabolism and structure of all parts of the body, the value of knowing more about lactate will be evident. It’s true that lactate, while normally activating and amplifying inflammation, as in arthritis, can in certain situations turn off the immune system. The very high lactate in tumors can change the cytolytic T cells from tumor-destroying to inflammation-promoting cells. When incoming cells experience the high lactate concentration near the tumor, their own energy production is suppressed, as in shock. The result is that immigrant cells, instead of correcting or dissolving the defective cells, accumulate and dedifferentiate, taking on different forms and functions.
>
> This ability to excite or to inhibit, depending on the surrounding energy economy in the organism, is operating in the brain during daily cycles of waking and sleeping, and in gradual processes such as the development of dementia. The recent demonstration of redifferentiation of heart cells to form stem cells when exposed to lactate (Ordoño, et al., 2020) probably has parallels in the maintenance of all tissues, including the brain—under the right conditions, metabolic regression supports constructive renewal.
>
> The healthy sleeping brain increases its glycogen stores, and the excited, waking brain reduces the stores, while also reducing glucose and increasing lactate. Histamine, which can cause insomnia, activates the breakdown of glycogen, and GABA, which stops neural excitation, increases glycogen (Pennington and Pentreath, 1987). Fully excited neurons expend energy at a very high rate, and in this momentary state can use both oxidative metabolism and aerobic glycolysis, emitting lactate into their surroundings. The astrocytes associated with them can absorb lactate, and are able to convert it back to glucose by gluconeogenesis, and can secrete that glucose for use by neurons.
### Source 9 — Hair Like a Fox: A Bioenergetic View of Pattern Hair Loss
Danny Roddy · Book · 2013
> This process occurs in two phases: the anaerobic phase and the aerobic phase. In the anaerobic phase (without oxygen), glucose (6 carbon atoms) is broken down into two pyruvate molecules (2 carbon atoms each) in the cell’s cytoplasm. In the aerobic phase (with oxygen), the two pyruvate molecules generated in the anaerobic phase are decarboxylated (carbon dioxide removed) and have lipoic acid molecules attached to them yielding two molecules of acetyl-CoA. The acetyl-CoA molecules then enter the Krebs cycle in the mitochondria, producing small amounts of energy before realizing the complete oxidation of glucose in the electron transport chain, where almost all the energy that could possibly be derived from glucose is derived. Cells without oxygen convert pyruvate to lactate, rather than acetyl-CoA, generating small amounts of energy in the process and allowing glycolysis to continue to ‘run’ in the absence of oxygen. This inefficient process, called glycolysis (or fermentation), not only generates many times less energy than oxidative metabolism does, but is also inflammatory. Lactate activates many mediators of inflammation, which are also incidentally involved in the genesis of baldness; in stark contrast, lactate does not accumulate during mitochondrial respiration but is instead removed from the blood.1 Mitochondrial respiration is approximately 93 percent more efficient than fermentation2 as far as energy is concerned; however, the advantage of the former process hinges largely on the “waste product” carbon dioxide. Carbon dioxide allows cells, tissues, and organs to better absorb oxygen, essentially “breathing oxygen into us.” The Danish physician Christian Bohr is credited for elucidating the details of this finding, showing in 1903 that carbon dioxide, produced by properly respiring cells, caused hemoglobin molecules (the proteins on which red blood cells bind and transport molecular oxygen) to release their oxygen atoms, increasing the availability of oxygen to cells (i.e., the Bohr effect). In this respect, carbon dioxide and lactate share an inverse relationship, evidenced by the fact that lactate levels are no higher during bouts of exertion as a person acclimates to a higher altitude, where oxygen levels are lower than they are at sea level. This phenomenon is called the lactate paradox.
### Source 10 — Lactate vs. CO2 in Wounds, Sickness, and Aging
Ray Peat · Newsletter · Aug 3, 2009
> Nutrition and other conditions of life were until fairly recently said to have no influence on health if the person consumed sufficient calories and a minimum amount of the essential vitamins, minerals, and protein. The cult of genetic determinism was so powerful that it wasn't affected by the facts.
>
> In 1932, a pediatrician, Alexis Hartmann (with M. Senn) in St. Louis, injected intravenously a solution of sodium lactate into patients with metabolic acidosis, and several of them survived—despite the fact that some of them were already suffering from an excess of lactate. The subsequent widespread use of lactate solutions in hospitals has contributed to the general denial of its toxicity.
>
> Hartmann and Senn used racemic lactate, that is, a mixture of D-lactate and L-lactate. Our own tissues produce mostly L-lactate, but they can produce small amounts of D-lactate; larger amounts are produced by diabetics. Intestinal bacteria can produce large amounts of it, and it has many toxic effects. Methylglyoxal can be formed from either form of lactate, and it is an important factor in the glycation of proteins. It can also be formed from MDA, a product of lipid peroxidation. Protein glycation is an important factor in diabetes and aging, but glucose, rather than lactate and polyunsaturated fats, is commonly said to be the cause.
>
> About 50 years ago, lactate was known to induce the formation of new blood vessels, and for a much longer time it has been known to cause vasodilation and edema. In 1968, it was shown to stimulate collagen synthesis.
>
> Normally, collagen synthesis and neovascularization are caused by lack of oxygen, but lactate can cause them to occur even in the presence of oxygen. Maintenance of a normal extracellular matrix is essential for normal functioning and cellular differentiation. Abnormally stimulated collagen synthesis probably accelerates tumor growth.[[52](#ref052)]
>
> Nervous and hormonal factors can cause lactate to accumulate, even without prior damage to the mitochondria.[[37](#ref037)] Psychological, as well as physical, stress and overactivation of glutamate receptors can cause harmful accumulation of lactate in the brain.
### Source 11 — The "Personality" of Male Pattern Baldness (Learned Helplessness)
Danny Roddy · Video Transcript · Aug 29, 2016 · https://www.youtube.com/watch?v=nsYDJt5CWRk
> And another paper, I won't read the entire thing, but they injected lactate into males and increased their prolactin levels and it caused anxiety, panic attacks. And so that is like when a low thyroid person produces less carbon dioxide, they're going to produce more lactic acid. It's going to increase the prolactin level. And one of prolactin's functions is to suppress the thyroid even more. So it's kind of like a vicious cycle that's pretty hard to break out of, to be honest. So you have to. I think it takes an extraordinary amount of effort, which we'll actually talk about in a second or two. So back to the negative affectivity when definitely online you see it a lot but probably with people you know or yourself like for instance looking one of the reasons this concept struck me kind of to my core was I felt like I was a super negative person and especially with some of you know my background I was in a band and when we would tour I would just be like a horror to be around like nobody wanted to hang out with me. because I was super argumentative, I was super negative about everything, and I just saw kind of the worst in every situation. And when I stumbled, I just probably a year ago, stumbled upon the psychology reference for something they call negative affectivity, which is the ability to scan the environment for things that you don't like, and then to bring them up. And so you probably can think of a lot of situations where this happens, or people you know, but I wanted to talk about, after we talk about negative affectivity, why that state is representative of stress and the antithesis of youth. So let's talk about negative affectivity, what it is. They say, negative affectivity is a broad personality trait that refers to the stable tendency to experience negative emotions. Individuals who are high in negative affectivity are more likely to report negative affective mood states across time and regardless of the situation. High negative affectivity individuals not only experience more feelings of dysphoria and tension, but have a negative view of self, report more semantic symptoms, and have an attention bias towards adverse stimuli. Overall, they seem to scan the world for signs of impending trouble. Tying it into physiology, a common denominator among the studies documenting increased cortisol to laboratory challenges appears to increase in negative affectivity.
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