# Glycation

Category: Metabolism

The attachment of a sugar to a protein.

10 passages · 1 author · 2008–2020 · Most-cited: [Ray Peat](https://bioenergeticoracle.com/md/voices/ray-peat/index.md)

Canonical page: https://bioenergeticoracle.com/concepts/glycation

## Synthesis

**Glycation** is the attachment of sugar molecules to proteins, but Ray Peat argued that most of the damage attributed to it is actually caused by **lipid peroxidation** of *polyunsaturated fatty acids* (PUFA), not by glucose itself. [Source 1, 3, 8] In controlled experiments, lipid peroxidation products damage proteins roughly 23 times faster than simple sugars do, and the fragments of deteriorating PUFA combine with proteins to produce immunogenic substances often misidentified as "advanced glycation end products." [Source 3, 8] Peat stated plainly that "most of the things that are called glycation are really fat-breakdown products," with the glycerol liberated by lipolysis being metabolized to **methylglyoxal**, a potent glycating agent. [Source 1, 6]

The process is intimately tied to the failure of oxidative glucose metabolism. When cells cannot oxidize glucose, they shift toward fat oxidation, producing less **carbon dioxide** and more lactate. [Source 2, 9] Carbon dioxide has a spontaneous ability to attach to the same reactive amino groups on proteins that sugars would otherwise occupy, meaning that when carbon dioxide is abundant, *glycation is directly blocked* by this protective carbamylation. [Source 2, 9] The failure of glucose consumption and carbon dioxide production, as seen in Alzheimer's disease, therefore predisposes tissues to glycation, which imitates mutated forms of proteins and promotes amyloid formation. [Source 2, 5] Glycation of collagen in the extracellular matrix alters its properties, making it a preferred site for glycated prion-like proteins, and is considered the major mechanism in the cross-linking characteristic of aging. [Source 2, 5]

The primary drivers of this pathological glycation are the PUFA and the hormonal stress state they induce. PUFA block glucose metabolism for energy, suppress thyroid function, and increase the liberation of free fatty acids, creating a vicious cycle where more glucose is produced adaptively but cannot be oxidized. [Source 1, 8] The oxidative breakdown products of PUFA—including **malondialdehyde**, **acrolein**, and **glyoxal**—damage mitochondria directly, further reducing the ability to oxidize sugar and produce protective carbon dioxide. [Source 4, 8] Peat noted that sugar often gets the blame for what PUFA do, citing the example of hemoglobin A1c (HbA1c), where most of the so-called glycation is really from oxidative breakdown fragments of PUFA. [Source 10]

Therapeutic intervention against glycation centers on restoring oxidative metabolism and blocking the underlying mediators of damage. Aminoguanidine, a recognized blocker of glycation, was found to achieve its effect by inhibiting **nitric oxide**, which leads to oxidative damage in blood vessels. [Source 7] Peat emphasized that shifting away from PUFA toward saturated fats, while eating frequently with sugar to avoid stress-induced lipolysis, allows the slow disposition of unsaturated toxic fats over a period of years, progressively restoring efficient metabolism and the protective production of carbon dioxide. [Source 6]

## People also ask

### What does Ray Peat identify as the true cause of damage usually blamed on glycation?

Peat argued that most damage attributed to glycation is actually caused by lipid peroxidation of polyunsaturated fatty acids (PUFA), with their breakdown fragments damaging proteins far faster than sugars and creating substances mistaken for advanced glycation end products.

### How does carbon dioxide protect against glycation?

The entry describes carbon dioxide spontaneously attaching to the same amino groups on proteins that sugars would target, so when oxidative glucose metabolism is strong and CO2 is abundant, this protective carbamylation directly blocks glycation.

### Why did Peat consider polyunsaturated fats central to glycation-related aging?

PUFA block glucose oxidation, suppress thyroid function, and their breakdown products damage mitochondria, creating a cycle where less protective carbon dioxide is produced and more pathological glycation occurs, driving the cross-linking characteristic of aging.

## Related concepts

- [Amyloid](https://bioenergeticoracle.com/md/concepts/amyloid/index.md)
- [The Randle Cycle (Randle Effect)](https://bioenergeticoracle.com/md/concepts/the-randle-cycle-randle-effect/index.md)
- [Antioxidants](https://bioenergeticoracle.com/md/concepts/antioxidants/index.md)
- [Association-Induction Hypothesis (Gilbert Ling)](https://bioenergeticoracle.com/md/concepts/association-induction-hypothesis-gilbert-ling/index.md)
- [ATP (Adenosine Triphosphate)](https://bioenergeticoracle.com/md/concepts/atp-adenosine-triphosphate/index.md)
- [Butter](https://bioenergeticoracle.com/md/concepts/butter/index.md)

## Cited passages

Passage numbers match the `[Source N]` markers in the synthesis above.

### Source 1 — Ray Peat Email Advice Depository — Post 546

Ray Peat · Email · Apr 2, 2019

> **Question:** It is said hyperglycemia is bad because it can cause damage to nerves, blood vessels, organs. Do you think the sugar itself can cause damage if its level is kept high in the blood stream for an extended period? There is a lot going on when the body is in a state of hyperglycemia, so it seems a little bit weird to blame any damage that is caused entirely on the sugar itself. Could it just be something else that happens to be high like FFA, insulin, lactic acid, or even an absence of something, like sugar (being utilized) or CO2?
>
> **Ray Peat:** In tissue culture experiments, very high glucose has harmful effects, but those conditions don’t reflect what happens in the whole organism. Glucose in the blood is increased adaptively to protect against something that’s damaging the tissues, and that’s usually a hormone imbalance that is interfering with the ability to oxidize glucose. The “glycation” that’s usually blamed on high glucose is mostly caused by lipid peroxidation from polyunsaturated fats, and the glycerol that’s liberated by lipolysis, and metabolized to methylglyoxal. The fats block glucose metabolism for energy, and more glucose is produced to overcome that.

### Source 2 — Energy Structure and Carbon Dioxide A Realistic View of the Organism

Ray Peat · Newsletter · 2013

> Cells related to inflammation can produce amyloid, as well as remove it. Glycation, the attachment of sugar molecules to proteins, can happen quickly, and can occur either with or without enzyme catalysis. The failure of glucose consumption and of carbon dioxide production in Alzheimer's disease predisposes to glycation.
>
> Glycation imitates mutated forms of proteins, for example normal transthyretin behaves like the prion protein, forming amyloid. Transthyretin, the protein that carries thyroid hormone and vitamin A, is normally taken up along with cholesterol under the influence of thyroid hormone. Abnormal cholesterol metabolism is one of the traits associated with Alzheimer's disease. In the absence of thyroid-supported respiration, carbon dioxide and other respiration-associated molecules (e.g., acetate) are replaced by lactate and unused sugar, causing abnormal modifications of proteins such as tau, which regulates microtubule assembly. Glycation of collagen in the extracellular matrix alters the properties of the matrix. The glycated matrix would become a preferred site for glycated prion-like proteins.
>
> It is possible that the altered transthyretin makes vitamin A less available to cells. Vitamin A deficiency creates major disruption of the framework proteins. Fragments of starch molecules inhibit the enzymes that remove inappropriately bound sugar molecules from proteins, and the inability to metabolize sugar into carbon dioxide increases that binding. Starches and unsaturated fats cooperate in this process of inappropriate sugar binding, while thyroid hormone, and the carbon dioxide it produces, tend to prevent the binding.
>
> Considering the universal importance of carbon dioxide to life, the ways it interacts with all of the important substances that make up organisms, that it is involved closely with ATP synthesis and other energy-related processes, that it participates intimately in the regulation of water and ions, that it is therapeutic in a range of conditions including angina pectoris, hypoxia, epilepsy, inflammation, shock, lipid peroxidation, pneumonia, and asthma, I think we can at least conclude that it is a largely overlooked mediator between chemical energy and life processes. In many cases, its movements and reactions constitute the actual motive force that so many fantasy theories have failed to explain. In other situations, it fills out the context for understanding the energy-mediating actions of ATP, calcium, and hormones.

### Source 3 — Unsaturated fatty acids: Nutritionally essential, or toxic?

Ray Peat · Article · 2008 · https://raypeat.com/articles/articles/unsaturatedfats.shtml

> Inflammation contributes to the decreasing ability to use oxygen, and the slowed renewal of proteins combined with lower ability to produce energy impair the organism's ability to control peroxidative damage and inflammation. The fragments of deteriorating PUFA combine with proteins and other cell materials, producing immunogenic substances. The so-called "advanced glycation end products," that have been blamed on glucose excess, are mostly derived from the peroxidation of the "essential fatty acids." The name, “glycation,” indicates the addition of sugar groups to proteins, such as occurs in diabetes and old age, but when tested in a controlled experiment, lipid peroxidation of polyunsaturated fatty acids produces the protein damage about 23 times faster than the simple sugars do (Fu, et al., 1996).
>
> Several autoimmune disease models in animals (involving the eye, kidney, and pancreas) have been prevented by a deficiency of the EFA (Schreiner, et al., 1989, Bazan, et al., 1990, Benhamou, et al., 1995). Besides causing a general slowing of metabolism, aging and toxic PUFA have specific actions on the detoxifying system. The enzymes that help to detoxify PUFA and estrogen and serotonin are inhibited by both PUFA and estrogen. All systems, including blood vessels and the intestine, are made leaky by estrogen and the PUFA and their products. A reduced ability to regulate the excitatory amino acids, resulting from PUFA toxins, tends to produce excitotoxicity, damaging nerves (Ou, et al., 2002).
>
> Although the interplay of the various types of nerve is very complex, a variety of experiments suggest that the PUFA are acting directly on serotonergic nerves, rather than just increasing the conversion of tryptophan to serotonin. For example, a deficiency of the so-called essential fatty acids, EFA, makes animals more sensitive to some anesthetics, and more resistant to others. It makes them resistant to the anesthetics that act by promoting the actions of serotonin, but it prolongs the effects of those that don't act through serotonin, and these are the anesthetics such as xenon and nitrous oxide, that apparently act by stabilizing the structure of water, as described by Linus Pauling.

### Source 4 — Generative Energy #35: CO2, Ketosis, and Mitochondria | PUFA, Sugar, Iron, and AGEs | Progesterone and Cell Stability

Ray Peat · Interview · Aug 29, 2020 · https://open.spotify.com/episode/2Iz99Wy5JmrbohNj4OZCxP

> ## Lipid Peroxidation and Glycation
>
> **Ray Peat:** By shifting the redox in that direction, I think it intensifies that methylglyoxal metabolism. Once you get that shift towards lactate, you're shifting against carbon dioxide, and carbon dioxide is a direct blocker of protein glycation.

### Source 5 — Energy Structure and Carbon Dioxide A Realistic View of the Organism

Ray Peat · Newsletter · 2013

> Cell proteins have an affinity for fats, and their hydrophobic surfaces tend to adsorb them. Unsaturated fats have a greater affinity for water than saturated fats do, and the location of the unsaturated bonds along the fat's carbon chain will affect the ways proteins interact with water. The fact that animal cells synthesize only fatty acids with a chain of eight fully saturated carbon atoms in their tails undoubtedly has something to do with the toxic effects of other unsaturated fats on the respiratory apparatus.
>
> The unsaturated fats that are so systematically disruptive to warm-blooded animals are characteristically produced in plants at relatively low temperatures. In organisms that live at low temperatures, they probably serve a function (among others) that is analogous to the function of estrogen in warm animals, namely, raising the structural temperature of water, modifying chemical activity by liberating water to some extent from the domination of the cellular proteins.
>
> One of the old theories of aging was that something (they called it metaplasm) accumulated in cells as a result of metabolism, the way ashes accumulate in a stove. Lipofuscin, or agepigment, is related to the oxidation of unsaturated fats, and has been proposed to be such a material, that progressively limits a cell's adaptive capacity because of its physical and chemical properties. Amyloid, a clear mass of protein deposited in and around cells, is another such age or stress-related material, that is currently being studied in Alzheimer's disease and other degenerative diseases. Glycation, the attachment of sugars to groups that otherwise could be occupied by carbon dioxide, seems to be a crucial factor in the formation of amyloid. (The term amyloid, in fact means starch-like.) Changes in the extracellular matrix, for example the cross-linking of collagen molecules, have been thought to cause some of the characteristic changes of aging, and again, glycation is the major mechanism in the formation of cross-links.
>
> In Alzheimer's disease, the commonly recognized features are tangles, amyloid deposits, hypometabolism, and evidence of inflammatory processes. Cells related to inflammation can produce amyloid, as well as remove it. Glycation, the attachment of sugar molecules to proteins, can happen quickly, and can occur either with or without enzyme catalysis. The failure of glucose consumption and of carbon dioxide production in Alzheimer's disease predisposes to glycation.

### Source 6 — Energy Production Diabetes Saturated Fats KMUD 2011

Ray Peat · Interview · 2011 · http://www.l-i-g-h-t.com/files/herb-doctors-energy-production,-diabetes-and-saturated-fats.mp4

> **Herb Doctor:** Is this glycation?
>
> **Ray Peat:** Yah. And most of the things that are called glycation are really fat-breakdown products.
>
> **Herb Doctor:** Basically, if you're a diabetic, then most likely you're going to be breaking down these bad fats in your tissues. You can get a blood test that shows that you have high lactic acid from this inefficient metabolism where you burn this fat (that’s really a bad fat, not a saturated fat) ?
>
> **Ray Peat:** Yah.
>
> **Herb Doctor:** What would happen if a diabetic only ate saturated fats?
>
> **Ray Peat:** Well, it takes a long time to use up the unsaturated fats; depends on how old and how fat you are. A thin person can change very quickly. It isn't just the storage fats that become very highly polyunsaturated with age, but every tissue contains phospholipids and other very complex molecules containing the fatty acids.
>
> **Herb Doctor:** So what would be, like, the maximum time? If someone who had cancer or diabetes or Alzheimer's? How long would it take if they stopped eating all of these unsaturated, polyunsaturated fatty acids, all these bad oils, and just started eating butter and coconut oil?

### Source 7 — Current Trends in Nitric Oxide KMUD 2015

Ray Peat · Interview · 2015 · https://www.youtube.com/watch?v=6TquRcpR8RY

> **Herb Doctor:** A person who I was speaking with earlier, who had amongst other things, one the main symptoms that they had was inflammation of both kidneys. And they had ureteral obstruction, retrograde urinary flow backing up into the kidneys producing a chronic or rather an acute kidney inflammation. And what I read in one of the PubMed articles was that the glomerulus, which is a functionary unit of the kidney, is unique in that the vascular networks have the potential themselves to express several of the called iso-forms of nitric oxide synthase, and can produce quite an amount of this in response to injury. In terms of the realistic inhibition of nitric oxide, I only found two compounds. One of them (Agmatine) I found advertised by Sigma Aldrich. (it's a fairly big - one of the biggest I think in America - chemical firm that will be charging a lot of money for a five milligrams sample). The other one, apparently, is almost as effective, but I think it has a slightly different mechanism, and that is Aminoguanidine. And if you look at that online (Aminoguanidine), it is actually sold as a blocker of the glycation process whereby sugars and proteins form these glycation end-products that are damaging...
>
> **Ray Peat:** That was it’s first recognized effect. But it turns out that it’s achieving that by blocking nitric oxide, which leads to the oxidation damage to all of the blood vessels.

### Source 8 — Glycemia, Starch, and Sugar in Context

Ray Peat · Article · 2009

> But if the stored fats happen to be polyunsaturated, they damage the blood vessels and the mitochondria, suppress thyroid function, and cause glycation of proteins. They also damage the pancreas, and impair insulin secretion.
>
> A repeated small stress, or overstimulation of insulin secretion, gradually tends to become amplified by the effects of tryptophan and the polyunsaturated fatty acids, with these fats increasing the formation of serotonin, and serotonin increasing the liberation of the fats.
>
> The name, glycation, indicates the addition of sugar groups to proteins, such as occurs in diabetes and old age, but when tested in a controlled experiment, lipid peroxidation of polyunsaturated fatty acids produces the protein damage about 23 times faster than the simple sugars do. And the oxidation of fats rather than glucose means that the proteins won't have as much protective carbon dioxide combined with their reactive nitrogen atoms, so the real difference in the organism is likely to be greater than that seen by Fu, et al.
>
> These products of lipid peroxidation, HNE, MDA, acrolein, glyoxal, and other highly reactive aldehydes, damage the mitochondria, reducing the ability to oxidize sugar, and to produce energy and protective carbon dioxide.
>
> Fish oil, which is extremely unstable in the presence of oxygen and metals such as iron, produces some of these dangerous products very rapidly. The polyunsaturated essential fatty acids and their products, arachidonic acid and many of the prostaglandin-like materials, also produce them.
>
> When glucose can't be oxidized, for any reason, there is a stress reaction, that mobiles free fatty acids. Drugs that oppose the hormones (such as adrenalin or growth hormone) that liberate free fatty acids have been used to treat diabetes, because lowering free fatty acids can restore glucose oxidation.
>
> Brief exposures to polyunsaturated fatty acids can damage the insulin-secreting cells of the pancreas, and the mitochondria in which oxidative energy production takes place. Prolonged exposure causes progressive damage. Acutely, the free polyunsaturated fatty acids cause capillary permeability to increase, and this can be detected at the beginning of insulin resistance or diabetes. After chronic exposure, the leakiness increases and albumin occurs in the urine, as proteins leak out of the blood vessels. The retina and brain and other organs are damaged by the leaking capillaries.

### Source 9 — Ask the Herb Doctor: Dementia and Progesterone

Ray Peat · Interview · Dec 21, 2012 · http://l-i-g-h-t.com/files/herb-octors-dementia-and-progesterone-60-mins.mp4

> ## Metabolic Energy and Stress
>
> **Andrew Murray:** I wanted to talk a little bit more about energy. If there's something we want to get across, it is the need for metabolic energy in our bodies. Every organism ultimately uses energy to convert chemicals into other chemicals, and all the cellular processes require a currency of some kind of energy. Ultimately, ours is oxidatively burning glucose. That's the best way of doing it, isn't it?
>
> **Ray Peat:** Yeah. Under stress, we can force our physiology over to burning fat instead of glucose. That causes several changes. It produces less carbon dioxide and is likely to produce a lot of breakdown products that can cause inflammation.
>
> **Andrew Murray:** And the carbon dioxide is useful. I think most people think of oxygen as being life-giving, but ultimately the oxygen is not particularly good for you, is it?
>
> **Ray Peat:** No. Most people have heard about the glycated proteins that people get in diabetes or aging—they call them AGEs (Advanced Glycation End products). Those stick to certain parts of protein molecules. It happens that carbon dioxide also has a spontaneous ability to attach to those same groups. If carbon dioxide is abundant, you can't get glycation because carbon dioxide is protecting that.

### Source 10 — Ask the Herb Doctor: Sugar Myths II

Ray Peat · Interview · Oct 21, 2011

> ## Fats, Sugar, and Diabetes
>
> **Andrew Murray:** What's your opinion on the possibility of regenerating islet cells in the pancreas?
>
> **Ray Peat:** Sugar itself, sucrose, is known to stimulate the regeneration of beta cells. That was in my newsletter about a year ago, describing the early treatment of diabetes with glucose and looking at new in vitro studies where sugar stimulates regeneration and polyunsaturated fats kill the beta cells. Sugar often gets the blame for things the polyunsaturated fats do, such as the glycation of hemoglobin (HbA1c). Most of the so-called glycation is really the oxidative breakdown fragments of the polyunsaturated fats.
>
> **Andrew Murray:** So a person's HbA1c could be lowered if they avoided all polyunsaturated oils?
>
> **Ray Peat:** Yes.
>
> **Sarah Murray:** A really bad example of a way to eat sugar is a donut: white flour (glucose) fried in canola, sunflower, or corn oil (PUFA). You have pure glucose and pure polyunsaturated fatty acids blocking your cells from using that glucose. A good example is ice cream with fresh fruit. There you have a saturated fat and the fruit providing fructose.

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