Ketogenic diet and Vitamin C: the 101

Vitamin C and ketogenic diet

Written by Amber O’Hearn (MSc Computer Science). Find more of her writings at www.ketotic.org

 

The Recommended Daily Allowances (RDA) for different nutrients were developed on Western diets, and therefore, high-carb diets.

Given that a ketogenic metabolism uses different metabolic pathways and induces cascades of drastically different metabolic and physiological effects, it would be astonishing if any of the RDAs are entirely applicable as is.

One micronutrient that seems to be particularly warranting reassessment is vitamin C, because vitamin C is biochemically closely related to glucose. Most animals synthesize it themselves out of glucose. It shares cellular uptake receptors with glucose. Some argue that because we don’t make vitamin C, we need to ensure a large exogenous supply.

I will argue the opposite: so long as we are eating a low-carb diet, we actually need less. On our way, we’ll briefly re-examine the relationship between vitamin C deficiency and insulin resistance.

Table of Contents

Micronutrients matter

There are particular nutrients people need to develop normally and stay healthy, that we can’t make in our own bodies, and so we have to get them from our diets. We only started recognizing this at the end of the 19th century. Before that, the germ theory of disease was new and exciting, and we wanted to explain all maladies as infections. However, we ultimately learned that some diseases come from malnutrition. The best exemplifiers of this are when people or other animals die for lack of one specific ingredient, as in pellegra, beriberi, rickets, and scurvy. These ingredients were named, initially, “vitamines”, meaning vital amines, but when it turned out they weren’t all amines, the name was shortened to “vitamins” [1].

Most dietary therapies are based on this notion, that significant health improvements can be made by adding enough of missing nutrients. This is effective when the baseline diet was grossly deficient, but when nutrient issues are not acute, traditional dietary therapies are little better than nothing in the face of diseases of civilization.

This is the crux of what makes a ketogenic (see more: ketogenic diet 101 How to make fat work for you ? ) diet uniquely powerful. It is not just about changing nutrient intakes. Indeed, even ketogenic diets can be poorly constructed nutritionally. What makes a ketogenic diet powerful is that it induces a complete change in metabolic strategy from the modern, high-carb diet. (See The medical-grade diet for more on why a ketogenic diet is a class of its own among “diets”.)

Micronutrient needs depend on the metabolic state

It turns out that micronutrient needs depend on whether your metabolic state is based more on dietary glucose or dietary fat, with endogenous ketogenesis in the latter. Not only do the biochemical reactions involved in producing energy rely on different substances, but the downstream effects of this create different environments that deplete nutrients at different rates. This means that in many cases, the established RDA has little bearing on the context of a ketogenic diet (see more: Kickstart your Basic Keto diet).

Hint
The RDA for micronutrients can be imprecise. Before supplementing, make sure you’re eating enough nutrient dense foods (e.g. shrimp).

Animals making their own Vitamin C make less when carbs are low

At this point it will be helpful to understand some facts about vitamin C synthesis. The reason we need to consume vitamin C at all is that we are one of the few species that have lost the ability to make it ourselves. This evolutionary change happened to primates before humans emerged, so we share it with other primates, as well guinea pigs, some bats, and there are non-mammalian examples as well. Evolution does not systematically drop functions that are merely no longer useful. Because this genetic mutation is spread across entire species, and has happened in multiple lineages [2], there must be a selective advantage in not producing it [3]. I will return to this in a later post.

Vitamin C is chemically similar to glucose, and its synthesis is intimately tied to glucose metabolism. You may have already read that vitamin C and glucose compete for uptake in cells. That’s based on the fact they their chemical similarity allows them to use the same cell receptor (Glut1) [4].

However, the connection is deeper than that. Vitamin C is made out of glucose. In animals that synthesise vitamin C, synthesis is downregulated exactly in fasting or low-carbohydrate conditions [5], or when glycogen is otherwise low [6].Notably, this is not the case in hibernation, where the reverse is true [7].

In other words, even in animals who synthesise their own vitamin C, synthesis is low in otherwise normal low-calorie or low-carbohydrate conditions. Note that these conditions would often also be lower dietary vitamin C conditions. This is interesting, because if optimal vitamin C levels were independent of carbohydrate intake, then we might expect to see the opposite. That is, we might expect to see more vitamin C synthesis in tandem with less carbohydrate intake in order to make up for the missing dietary component.

The fact that vitamin C synthesis is downregulated when food or carbohydrates are low suggests the following hypotheses. First, it suggests that vitamin C might be more necessary in a glucose based metabolism. Second, it suggests that there are compensatory mechanisms that come into play when vitamin C is low that are also triggered by low-carbohydrate conditions, and therefore, vitamin C requirements are lower in low-carbohydrate conditions. Third, it suggests that high levels of vitamin C may even be detrimental under low-carbohydrate conditions.

I’ll leave the final one for a subsequent post, but let’s look at the first two.

Vitamin C is more necessary when glucose is high

It was proposed in 1975 by Mann and Newton that vitamin C transport across cell membranes may be impaired by glucose and suggested that diabetes may be a form of mild, chronic, localised scurvy [8]. Since then it’s been shown how glucose and vitamin C compete for uptake in cells and how strikingly well the symptoms of diabetes and heart disease can be explained as latent scurvy [9].

It’s been shown (same paper) that infusions of high levels of vitamin C can mitigate the hyperglycemia-induced deficiency to a degree. So in that sense, vitamin C is definitely “more necessary” when glucose is high. It is plausible then, that a diet very low in carbohydrate would require less vitamin C, for two reasons. First, blood glucose values will be lower on average, meaning that there will be a more favourable ratio of vitamin C to glucose, even at the same vitamin C level. Second, in ketosis, many cells are taking up ketones for fuel, and therefore much less glucose needs to be taken up.

Hint
Your essential micronutrients are involved in the chemical reactions happening inside you all the all the time. How much you need can change significantly depending on aspects of your diet (e.g. lots of sugar or only a little?)

Endogenous antioxidants glutathione and uric acid spare Vitamin C

Vitamin C can be spared by something that takes over one of its functions, or by something that increases its effectiveness.

Vitamin C has multiple distinct functional roles

Vitamin C serves many functions; new discoveries and hypotheses are still being made. It is well established that it can serve as an antioxidant in vitro, although its antioxidant action in actual humans has not been confirmed [10]. More particularly, it has not been established that increasing exogenous vitamin C intake has an antioxidant effect.

Perhaps the most important function of vitamin C is that scurvy does not occur in its presence. It is postulated, and widely believed that this is due to its role as a cofactor in hydroxylation reactions, though this is also unclear [11].

Ketogenic diets increase biosynthesis of glutathione

Even those that can’t synthesise vitamin C, can make more efficient use of it under the right conditions. In fact, scurvy can be substantially delayed in guinea pigs in the absence of dietary vitamin C, if glutathione esters are given. In one such experiment there was no sign of scurvy after 40 days, even though they usually die of it in 21-24 [12]. That’s because one of the functions of glutathione is its essential role in vitamin C recycling [13].

We know that ketogenic diets upregulate glutathione biosynthesis [14]. It’s unclear to me from the literature whether total levels are increased. In rats, it goes down in liver tissue, but up in hippocampal mitochondria [15].

It’s clear, however, that in addition to recycling vitamin C, glutathione has overlapping functions with vitamin C as an antioxidant and that they mutually spare each other [16]. I hypothesise that in ketogenic conditions, other antioxidants such as glutathione take over many functions that would be served by vitamin C in synthesisers.

Another candidate for this is uric acid.

Uric acid is similarly sparing of Vitamin C

Another mutation that humans and primates share is a loss of function of the uricase enzyme. Uricase breaks down uric acid, and the result of this mutation is higher uric acid levels in primates. Just like with the loss of vitamin C synthesis, there is good reason to believe that this mutation conferred a selective advantage, but the nature of that advantage is controversial. In an upcoming post, I will review the state of that controversy.

One hypothesis is based on the antioxidant properties of uric acid. This was put forth by Bruce Ames et al. in 1981 [17]. The idea is that because uric acid is a major antioxidant (more potent than vitamin C, for example) [18], its higher levels might explain the relatively long lifespans that apes have [19].

The uric acid mutation occurred in primates tens of millions of years after the vitamin C mutation, but it is plausible that they are related, that increased uric acid was of particular advantage in the context of lack of endogenous vitamin C. Regardless of whether its antioxidant role sufficiently explains the selective advantage of high uric acid, those antioxidant properties still stand.

ketogenic diets decrease oxidative stress

Producing energy produces free radicals, but this is less true when fat and ketones are the energy source than when glucose is [20]. This is one reason that ketogenic diets improve outcomes in traumatic brain injury [21].

So, we would expect the role of exogenous antioxidants to be less critical in a metabolic state that endogenously decreases oxidative stress.

Hint
Vitamin C isn’t the only anti-oxidant our body uses, in fact many anti-oxidants are made internally. How much Vitamin C you need also depend on how much of the other anti-oxidants there are.

What’s the relationship between insulin resistance and Vitamin C deficiency?

Given the above observations, that, on the one hand, some symptoms of diabetes and heart disease (i.e. of metabolic syndrome or insulin resistance) can be viewed as latent scurvy, and on the other hand, that the antioxidant properties of vitamin C in vivo are replaceable, it suggests another way of looking at the relationship between vitamin C and insulin resistance.

Linus Pauling famously believed that the diseases of civilisation were curable by high doses of vitamin C, but in practice, this has not consistently panned out. What if Pauling was right in the sense that an important underlying mechanism of those diseases is that insulin resistance reduces the access of tissue to vitamin C, causing many of the symptoms we associate with diseases of insulin resistance? There is much suggestive evidence about the relationship between vitamin C deficiency and hypertension, fasting blood glucose, and fatty liver disease, for example. This could explain why vitamin C infusions have inconsistent results. It is a band-aid solution; it doesn’t address the underlying problem, which is glucose overload, and impaired uptake of vitamin C. The popular hypothesis that the (inconsistent) beneficial effect of vitamin C in these diseases is a result of antioxidant properties, could be replaced by the simpler hypothesis that high intake of vitamin C can sometimes compensate for the scorbutic effect of glucose overload and insulin resistance.

Vitamin C requirements are probably much lower on a ketogenic diet

  • The amount of vitamin C required just for preventing scurvy was determined to be 10 mg a day, and that was determined in a high-carb context [22]. Subsequently, a nearly tenfold inflation of this recommendation is based on speculative data about the ability to derive antioxidant properties from vitamin C, and the effect it could have on mitigating blood sugar complications of a high-carb diet [23].
  • Insofar as antioxidant effects are important, these are likely to be met more powerfully by uric acid, glutathione, and the natural antioxidant consequences of low-carb diets, rather than exogenous supplementation.
  • The inflated recommendations for vitamin C intake are likely to be completely inapplicable to a person following a ketogenic diet, because that person can use much smaller amounts of vitamin C efficiently.

Acknowledgements

Many of these ideas were developed through conversations with Nick Mailer. Mistakes are my own.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Break Nutrition not only produces high-quality original content on the science of health and nutrition, we also introduce you to great science writers. Amber O’Hearn is both data savvy, a whiz with computers and rigorous in her search for evidence. These are ideal qualities for synthesizing deep dives into scientific topics relating to health and nutrition. I hope you enjoyed her work.

Feel free to explore her extensive reference section detailing the most relevant information within the references used in this article.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 

7 comments On Ketogenic diet and Vitamin C: the 101

  • I have asymptomatic hyperuricemie on my keto diet. Do you think that it’s normal and I have nothing to worry about? My terapeut says that it could cause a gout attack and wants me to take allopurinol. I didn’t want to, so I tried to return to a “normal” carb diet for couple of days. My uric acid went down rapidly. Now I came back to ketosis, drink a lot of water, eat less red meat etc, my UA is around 7 mg/dl. Today I bought vitamin C 100 mg, but now I am not sure if I need it…

    • Hi Dem,

      In order to answer your question I would have to find out much more about your medical background. What drugs do you take, if any? Are you diabetic? Nevertheless, returning to a “normal carb diet” doesn’t seem like a road to getting to the root cause of your hyperuricemia because there’s nothing about an absence of carbs that causes hyperuricemia as far as I know. It may be worth considering elements in your diet (& lifestyle) that may be inflammatory or causing undue oxidative (e.g. high fructose, vegetable oils, smoking…)

      Especially if you’re asymptomatic, I wouldn’t put too much time experimenting into Vitamin C – but it’s not dangerous so it’s not the end of the world if you do. Maybe consider a few of the usual suspects here (https://en.wikipedia.org/wiki/Uric_acid#Causes_of_high_uric_acid) and see if any lab tests can illuminate a point to improve.

      Good luck!

      • I am not diabetic, don’t take any drugs, I used to smoke for 20 years but gave up 4 years ago. My first experiment with carbs was about three days and I ate only starchy carbs, no sugar. My UA level was very low. I also tried to carb up last Saturday – with sweet donuts (Kiefer protocol), next day my fasting UA was 11 (!), so fructose is definitely a bad guy. But I realized that if I drink glass of water my UA goes down very quickly (15 min later it is 7). So now I don’t scare my doctor a lot.

  • Hi Dem
    According to Prof. Stephen Phinney, it can take several weeks, if not months, to fully keto-adapt and during this period, your uric acid may be high. Asymptomatic hyperuricaemia does not need treating in the absence of tophi (crystals of urate in the tissues). IMO, you don’t need allopurinol (I am a Rheumatologist). I once saw a 21 year old man who suffered from severe gout. There was clearly a strong genetic component as there was a family history of gout. I saw him a year after he had put himself on a VLCKD whilst at University. He had not suffered a single attack of joint pain whilst on his new diet, which, interestingly did not feature much red meat but included quite a lot of eggs, fish and seafood. His serum uric acid level had fallen but was still in the upper range of normal.

    • Thank you for your answer, Dr Haynes.
      I’ve been on LCHF for the last 3 years and a half. My UA level in the previous blood tests was also in the upper part of normal, except the last one.
      During last week I’ve realised that I can normalise UA level mainly by decreasing caloric deficit. Drinking more water and doing more aerobic exercises could also be helpful. But eating enough and escaping long fasting are most likely more important in my case. I monitor my UA everyday during last week and it raised higher than 7 mg/dl (8) only once.
      I hope that I’ll never realise what gout is. Now I know a lot about it.

  • Hi, Dem. This is not meant to be medical advice, of course, but my personal opinion is that hyperuricemia, if asymptomatic, is not only benign, but potentially beneficial. I have an upcoming post on this. I’ll link to it here when it is posted.

    • Thank you all. My hyperuricemia wasn’t asymptomatic, I’ve realised that just now after at least three gout attacks before I started my keto and one after. They all weren’t typical, just pain in ankle that appeared without any reasons in the mornig. I didn’t have visible changes around joint and I thought it was sprained ankle (somehow). I’d been having pain only getting up and walking, no pain in rest and two-three days later all symptoms suddenly disappeared. Now I can explain small symptoms: dermatitis reactions on chocolate and high intensity training …
      So, I am really sorry if I scared someone from our keto community, I was scared too:(
      Now I need to understand how to live in Czech Republic not drinking beer (we have zero carb), what to do with two boxes of Cianti (my friends will help me, I’m sure) and how to work out. The last point is not a joke, unfortunately 🙁

Leave a reply:

Your email address will not be published.

Site Footer