Methylglyoxal regulates glycolysis in a way that prevents dangerous accumulation of glyceraldehyde, and that conserves glucose during carbohydrate restriction. Its rise on a low-carb Atkins diet makes physiological sense because it conserves glucose and even allows gluconeogenesis from fatty acids. Nevertheless, high methylglyoxal levels causally contribute to diabetes, and this seems to be a stress response that should not be chronically elevated.

Mastering Nutrition Episode 13: Wait a Second, Is Glycation Actually GOOD For You?

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Methylglyoxal regulates glycolysis in a way that prevents dangerous accumulation of glyceraldehyde, and that conserves glucose during carbohydrate restriction. Its rise on a low-carb Atkins diet makes physiological sense because it conserves glucose and even allows gluconeogenesis from fatty acids. Nevertheless, high methylglyoxal levels causally contribute to diabetes, and this seems to be a stress response that should not be chronically elevated.


In this episode, I wrap up glycation week by discussing why glycation may play essential physiological roles in the body.

In the early days of methylglyoxal research, Albert Szent-Gyorgyi, who won the 1937 Nobel prize in Physiology or Medicine for his discovery of vitamin C and critical steps in energy metabolism, saw the molecule as part of a regulatory system. In the early research into glycolysis, the system that converts methylglyoxal to pyruvate was seen as part of energy metabolism. Only later did glycation become synonymous with toxicity.

Current science can be used to make a compelling case that methylglyoxal is normally produced as part of glycolysis to prevent a dangerous buildup of glyceraldehyde and that it rises during carbohydrate restriction to help preserve much-needed glucose and to enable the conversion of fat to additional glucose. This could be seen as an elegant system of regulation and a key part of energy metabolism.

Nevertheless, it is unclear where the dividing line between physiology and pathology lies, and I see the apparent rise of methylglyoxal during carbohydrate restriction as part of a stress response that should not be chronically activated.

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Read on for the show notes.

Show Notes for Episode 13

This episode, while not terribly long, is pretty rich in biochemistry. If you don't want to listen to the whole thing, use this to navigate:

1:00 Follow me on Snapchat (chrismasterjohn) for sneak peaks of PUFA report and other things I’m working on
1:15 I’ll be LIVE on Facebook this Saturday, June 11, 2:00 PM Eastern time
1:50 Cliff notes
5:00 Diversify your work positions! I recorded this standing.
5:20 Like reactive oxygen species or inflammation, whether glycation contributes to health or disease depends on context
8:00 The early days of research attributed roles in cellular regulation and energy metabolism to methylglyoxal
11:05 Methylglyoxal glycates a glycolytic enzyme in a way that prevents dangerous glycolytic intermediates from accumulating.
20:00 Methylglyoxal increases when carbohydrate is limiting, and its inhibition of glycolysis helps preserve glucose for the tissues that most need it.
23:50 During carbohydrate restriction, methylglyoxal allows the conversion of fat to much-needed glucose, with the help of glutathione.
25:08 Practical strategies to boost glutathione
27:40 Back to methylglyoxal as a source of glucose.
34:00 Is the rise of methylglyoxal during carbohydrate contraction physiological, pathological, or both? Is it a stress response that is good but should not be chronically elevated?
36:40 Insulin plays too many critical roles for it to be chronically maximally suppressed, so I err on the side of believing this is a stress response that we do not want to be consistently activated.

All of this is extensively documented in my doctoral dissertation and to a large degree in my other writings linked to in my Start Here for Glycation and AGEs post.

Has this episode changed your view of glycation at all? What do you think of the study showing an increase in methylglyoxal on the Atkins diet? Does this episode change how you would view that study at all?

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  1. Hi Chris, I love your podcast and the info you provide. I’ve enjoyed listening to your reasoning from the cholesterol series with CK to the methylglyoxal stuff you did for ahs? one time I think. Anyway, I’ve a couple of q’s. 1) (on topic) being based in NZ, I’m familiar with methylglyoxal as it’s the active ingredient in Manuka Honey. I’m interested to know what you think about nutritional methylglyoxal as it gets marketed as “the bees are bringing us medicine, nature is the answer regardless of the question” and has been touted by some as a complimentary treatment for everything up to and including cancer.
    2) (off topic) I loved your 2 podcasts explaining insulin resistance and how it describes energy excess not just carbohydrate excess. The part on the liver getting bathed in fat resulting in secretion of glucose straight into the bloodstream was fascinating. I was wondering if part of the homeostasis people achieve (and the notorious plateau) maintaining a high fat low carb diet might be blood sugar stability because of this glucose secretion into blood by the liver as the fat is causing insulin resistance in the liver prompting GNG and as the liver has nowhere to store glycogen as you outlined. If this is the case, it seems to be a questionable trade-off to game the liver into being a somewhat accidental source of blood sugar at the expense of possibly aiding fatty liver. Anyway sorry for the wordy, ramble. Love your work, thank you very much for the info.

    1. Hi Craig,

      I think it makes sense that methylglyoxal would have antimicrobial properties and contribute to those of manuka honey.

      I’m not sure what your second question is, but I agree it is undesirable to promote chronic gluconeogenesis.


      1. Thank you for the reply Chris. I guess my question is: “what is the mechanism by which high fat (possibly moderate/low protein) diets achieve satiety and blood sugar control? Is it helped by increased HGP as happens as you pointed out when the liver has nowhere to store glycogen?

        Thanks very much

        1. Hi Craig,

          I don’t know what HGP is.

          I don’t recall ever saying high-fat diets help blood sugar control. In most cases where that is actually observed (which definitely is not all cases of a high-fat diet by any means), it is probably due to weight loss. Absent that, in a healthy person, fat slows gastric emptying and moderates the carbohydrate entrance into the blood stream, but that’s not necessary to prevent hyper- and hypoglycemia in a healthy person. In diabetics, that effect doesn’t even occur. And it’s common for people to develop high blood sugar on a low-carb high-fat diet.


          1. Hi Chris,

            Sorry for being confusing.

            I realise that low carb, high fat eaters show poor glucose control and they can have high blood sugar levels. I wondered, based on your podcast, whether the perceived satiety may be caused by this high blood sugar (caused by Hepatic Glucose Production the HGP I referred to) if that is the case I think it would have pretty huge implications.

            Thanks again Chris, do you have a patreon?

          2. Hi Craig,

            While I do think low blood sugar stimulates appetite, I don’t think higher-than-normal blood sugar stimulates satiety. Though Stephan Guyenet would be a good person to ask about this.

            I don’t have a Patreon, but if you use Amazon you could “donate” some money to this site by going there through

            And I’ll have stuff you can purchase later in 2017.


  2. Narsis:
    Since dairy products have high insulin index and they also have sugar, does a diet based in dairy products and meat without carbohydrate is enough for achieving the health benefits of insulin? ( as you know there are so many Tribes and nations in which their diets based primary on milk and meat ).

    1. Hi Narsis,

      No, the insulin index is not important and the insulinogenic effect of meat doesn’t count. But milk has carbs, and it is the carbs that are important.


  3. For a while, I was eating a very high amount of fructose (200g of sugar per day) from lots of polyphenol rich fruits — dates, plums, pomegranate, berries, melons, etc. with buckwheat honey, dark molasses, etc. During this time, I included a lot of cheese / dairy in my diet, coconut oil, and lots of saturated-fat rich meat (eg. bacon, organ meat, ground beef.) After hearing Lustig and others talk down sugar, I switched to consuming more starch and much less fruit — rice, tubers, legumes, etc. After noticing my blood sugar spike over 140-160 mg/dL for 30-45m after a meal and hearing Gundry, Rosedale, and others talk down starches, lectins, and animal protein, recommending low levels of insulin, I switched to primarily eating plant-based fats and getting protein from nuts / vegetables with ketones consistently resting between 1.5-3.0mmol/L BHB with carbohydrate and calorie restriction. Then, once learning apoE4 status and noticing an elevated LDL-P flag on a blood test and learning of the LDL-raising effect of animal-derived long-chain saturated fat, this became a high PUFA/high MUFA HFLC nearly-vegan pescitarian diet, lately with supplemental C8 MCT oil and a 6-hour eating window + 18hr daily fast. Now that I’m hearing about methylglyoxal production from calorie/carbohydrate restriction/fasting/ketosis and the dangers of PUFA consumption, I’m not quite sure *which* way to go with my diet. It seems like I don’t want to eat much SFA, or much PUFA, or much sugar, or much starch… or much animal protein… or much plant protein… or elevate ketones… or restrict calories… or fast. The more I learn, the less sure I am about *any* dietary strategy beyond eating whole foods.

    How would you approach your diet / exercise / supplement regimen with these things in mind? Using diet + exercise + supplementation, how does one maximize insulin sensitivity and glutathione synthesis, optimizing lipids (LDL-P/sdLDL/TGs/HDL), minimizing A1C / glycation / oxidative stress / inflammation, while also reaping the benefits of a ketogenic low-insulin, calorie-restricted diet?

  4. Terry Ritter wrote this in a comment that got left in Blogger during the migration:

    “Great podcast. I just came upon your work and am enjoying…especially the biochemistry. My question, which centers on your advocacy of some insulin in the system to maintain all the positive aspects it seems to promote, how are the tribes and populations that have historically had very little access to carbohydrates able to live vibrant lives per the observations of the scientist that observed them? Is there other mechanisms that the body can use to accommodate this low carbohydrate/low insulin state? “

    1. Terry,

      I do think they experienced lower thyroid hormone output from less carbs. For example, Price reported that the natives of the Arctic had most of their children born in June because the moose mated 9 months earlier and they would hunt the moose for their thyroid glands (which enlarge during moose mating season), consume the thyroid glands, and the thyroid would induce conception. So I see that as self-medicating with thyroid hormone to compensate for the severe restrictions of the environment.


  5. Is there a downside to using leucine as a way to trigger an insulin response on low carbohydrate diets? How would this affect glycation?

    1. Todd,

      I believe leucine is likely to stimulate glucagon in addition to insulin. Glucagon counteracts most effects of insulin, so I would not consider protein or leucine sufficient to replace carbohydrate.


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