Lactate and the Lipoic Acid Flu, An Hypothesis and n=1

In my last post I recommended a strategy of combining lipoic acid – a natural, mitochondrially produced substance which oxidizes NADH to NAD+ – and succinate, which drives mitochondrial ROS production and oxidation of NADH to NAD+ via the activity of the enzyme NNT. Both of these are designed to shift the redox pool of NADH to a more oxidized state as defined by a high NAD+/NADH ratio. High levels of mitochondrial NAD+ should activate SIRT3, leading to the deacetylation of our mitochondrial enzymes. NAD+ is also a required co-factor in the citric acid cycle. The more mitochondrial NAD+ you can regenerate, the faster you can run your metabolism.

Since that post I’ve been lurking over at the Reddit r/SaturatedFat to hear people’s experiences. One of the things people have been reporting are symptoms resembling the so-called “keto flu” – headaches, lethargy and sometimes even nausea. With most these symptoms seem to subside within a few days as they adapt. Someone suggested that perhaps the symptoms were due to dropping blood glucose level, although no one was reporting a rapid drop in blood glucose due to either supplement. I suspect the symptoms could be due to rapidly dropping lactate levels.

In theory, succinate and lipoic acid should have the same effect on NADH/NAD+ ratios and lactate levels, but a lot more is known about the effects of lipoic acid than succinate, so I’ll focus there. I also like the alliteration.

Lactate as a Circulating Redox Buffer

The traditional view of metabolism is that glucose enters a cell, is broken into two molecules of pyruvate via glycolysis and the two pyruvate molecules are shuttled into the mitochondria to be fully oxidized. This recent review​1​ presents an alternative viewpoint. In most cells glycolysis and mitochondrial respiration are uncoupled. Monocarboxylate transporters (MCTs) are rapidly excreting and re-uptaking lactate and pyruvate.

In the cytoplasm, lactate dehydrogenase catalyzes the reversible reaction of converting lactate to pyruvate while reducing NAD+ to NADH. This reaction is controlled by the relative ratios of NAD+/NADH and lactate/pyruvate. A cell with a high cytoplasmic NADH/NAD+ ratio imports pyruvate, reduces it to lactate – converting an NADH to an NAD+ – then exports it, thus lowering it’s NADH/NAD+ ratio.

The authors suggest that glucose serves as a fuel for specific tissue types that require it but that lactate is the true universal carbohydrate fuel.

in mammals, lactate also serves as a major circulating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues. This reconceptualization of lactate as a fuel—analogous to how Hans Christian Andersen’s ugly duckling is actually a beautiful swan—has the potential to reshape the field of energy metabolism.

Joshua D. Rabinowitz  and Sven Enerbäck. “Lactate: the ugly duckling of energy metabolism”

The authors go on to suggest that overall levels of lactate are largely affected by the activity level of pyruvate dehydrogenase (PDH) – the mitochondrial enzyme that converts pyruvate to acetyl-CoA, initiating mitochondrial respiration. To say this simply, when pyruvate is oxidized in the citric acid cycle, circulating levels of lactate drop. PDH controls the rate at which pyruvate can be oxidized.

I previously wrote that PDH activity is low in both torpid animals and obese humans due to its inhibition by PDK4, which phosphorylates it and turns it off. In turn, PDK4 is activated by NADH and Acetyl-CoA.​2​ In obesity, buildup of mitochondrial NADH leads to fewer turns of the citric acid cycle, which allows acetyl-CoA to build up. The acetyl-CoA and NADH activate PDK4 which phosphorylates PDH and turns it off.

Lactate In Obesity and Diabetes

Fasting lactate and pyruvate levels are increased in obese and obese diabetic humans:​3​

LeanObeseObese Diabetic
Blood Lactate (mmol/l)1.782.262.76
Blood Pyruvate (mmol/l)0.060.090.13
Blood Glucose (mmol/l)4.54.811.7

Lipoic Acid Reduces Circulating Lactate

Obese, diabetic patients who took 1200mg (600mg twice a day) of lipoic acid for 4 weeks saw a significant drop in circulating lactate both in the fasted state and in response to an oral glucose tolerance test.

Lipoic acid supplementation dramatically lowered lactate levels in obese, diabetic humans during an oral glucose tolerance test while having a relatively small effect on blood glucose.

R-Lipoic acid allows the direct oxidation of mitochondrial NADH to NAD+. NAD+ allows the citric acid cycle to cycle, reducing acetyl-CoA. Lowered NADH and acetyl-CoA increase PDH activity. Increased PDH activity allows more lactate to be fully oxidized (as pyruvate). When lactate is being burned in any tissues, systemic lactate and pyruvate levels drop due to the rapid flux in and out of cells.

Lactate, Nausea and Headaches

According to Wikipedia, Ringer’s lactate solution (RL), also known as sodium lactate solution and Hartmann’s solution, is a mixture of sodium chloride, sodium lactate, potassium chloride and calcium chloride in water. It has been in use since 1930 and is on the Wold Health Organization’s list of essential medicines. Ringer’s lactate is the standard of care for preventing post-operative nausea.​4​ It is also sometimes used for headaches.​5​

An n=1

All of this gives me an idea for an n=1 to wedge between Thanksgiving and Christmas. I bought a blood lactate tester over a year ago and have barely used it. I’ve been going through a washout period (no supplements) to establish a baseline to do a better n=1 with lipoic acid and Succinade. I’m going to collect baseline levels of lactate throughout the day for three days, followed by escalating lipoic acid. When I’ve hit 2400mg, I will plateau and escalate Succinade. I’m still thinking through details, but I like the idea of lactate as an indicator of PDH activity.

Conclusions

I suspect that a rapid drop in lactate levels could causes symptoms such as headache, nausea and lethargy. I also suspect that dropping lactate levels are an indirect indicator of increased pyruvate dehydrogenase levels: moving away from torpor. We know that lipoic acid drops lactate levels in the medium term, but I’m going to see how it behaves in the short term – minutes to hours – and if succinate will have a similar effect on lactate.

  1. 1.
    Rabinowitz JD, Enerbäck S. Lactate: the ugly duckling of energy metabolism. Nat Metab. Published online July 2020:566-571. doi:10.1038/s42255-020-0243-4
  2. 2.
    Pettit FH, Pelley JW, Reed LJ. Regulation of pyruvate dehydrogenase kinase and phosphatase by acetyl-CoA/CoA and NADH/NAD ratios. Biochemical and Biophysical Research Communications. Published online July 1975:575-582. doi:10.1016/s0006-291x(75)80185-9
  3. 3.
    Konrad T, Vicini P, Kusterer K, et al. alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care. Published online February 1, 1999:280-287. doi:10.2337/diacare.22.2.280
  4. 4.
    Salman N, Aykut A, Sabuncu Ü, Şaylan A, Yağar S, Şekerci S. Dextrose administration may reduce the incidence of postoperative nausea and vomiting after laparoscopic cholecystectomy: a double blind randomized controlled trial. Minerva Anestesiol. Published online April 2020. doi:10.23736/S0375-9393.20.13484-9
  5. 5.
    Carter BL, Pasupuleti R. Use of Intravenous Cosyntropin in the Treatment of Postdural Puncture Headache. Anesthesiology. Published online January 1, 2000:272-272. doi:10.1097/00000542-200001000-00043
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29 thoughts on “Lactate and the Lipoic Acid Flu, An Hypothesis and n=1”

  1. Hmm…my mind first went to metformin (and maybe berberine?), which apparently increases circulating lactate. How does that fit into the story? The paper above (ref 3) says that the patients who were taking metformin were taken off it a couple of weeks before this study. I wonder, if taken together, this effect would be cancelled out – although I don’t know the relative magnitudes of the effect. Does metformin increase lactic acid to the same extent as LA decreases it?

    The other thought I had was again about NR or NMN supplementation. I know you wondered whether increasing the pool size of NAD+ might not make a difference on its own… but I do wonder if it might…. as you say “NAD+ allows the citric acid cycle to cycle, reducing acetyl-CoA.”

    I’m not deep into the biochemistry though as some of the other commenters here and on reddit are, so this is some high level hand waving here.

    1. Thank you for asking this. I’m very interested as well, as I take Metformin and was considering adding R-ALA to my regimen.

      Jenn

    2. Yeah, I’ve also wondered if the effects of berberine/metformin might limit the usefulness of this approach, since you can’t drive ROS if complexI is partially blocked. Probably worth doing a post on…

  2. Lactate, hmmm… I was born allergic to all milk, almost died of starvation till the geniuses around me figured it out and put me on soy, what IS lactate? is it like lactic acid when you exercise too much? or is it like lactose as in lactose intolerant .. sorry, i just woke up, it’s probably neither, seems a natural byproduct of things, but i just wondered why they call nursing mothers ‘lactating’, maybe i have a sort of vestigial tail of childhood allergy left? and if i did, would it matter? ok, need coffee… thanks for this, Brad!!

    1. Hi Elaine! It’s a good question, actually! Lactose is a sugar found in milk. Lactate is a fermentation product, that was initially found in cheese or some fermented dairy product, hence the similar name. But we all have circulating lactate and yes it is what builds up in exercise.

  3. I’ve been taking 1,200 mg lipoic acid in the morning with my coffee, then one scoop of succinate prior to my first meal (lunch). The things I’ve noticed:

    – The lipoic acid upsets my stomach/makes me hungrier.
    – The succinate has to be taken with a lot of water, else I get sick to my stomach.
    – It’s hard to remember to take succinate an hour before eating, just based on my particular schedule.
    – Effects are unclear. Temperature is ambivalent. If temp does increase, it takes hours. For instance, I took succinate around 10am; just took my temp and it was: 96.3 at 9:18am (got into work); 96.8 at 12:26pm; 97.8 at 2:09pm.
    – I did not take my temp before starting the regimen, so it could be this is normal for me. I made the mistake of not getting a good baseline.
    – I did take 1/2 scoops morning and night for one day, but got hot at night and had poor sleep. Decided only one scoop during the day for this week. Not sure if the poor sleep was succinate-related or random.
    – Seems to cause hard defecation for me. Unusual.

    I’m still testing. Will add in a 1/2 scoop in the evening at some point.

    1. Oh yeah, did have to take an allergy pill and an advil the other night, which never happens. I can’t remember the last time I took either one; last year sometime, I think.

      1. After reading that Reddit thread, I guess I should have been taking my temperature in the morning instead. I’ll have to try that.

  4. I remember reading about the idea of lactate as part-processed carbs (here?) and liking it. Seems analogous to ketones being part-processed fats. Between the two of them, they create a flexible way of starting the burning of fat or glucose in a place in the body that has plenty, then moving the intermediate (lactate / ketones) to a different part of the body (optional), then finishing the burning. Seems very neat.

    1. That is correct, but what’s even cooler is that cells can equilibrate their NADH/NAD+ ratios by taking in pyruvate and releasing lactate (which converts NADH to NAD+) or vice-versa.

    2. Thinking out loud here… And this might be Capt. obvious/oblivious.

      Given that muscle exertion produces lactate. Could the lactate be doing a few things here?
      1. Saturating the cell with the primary particle it needs to be able to ramp up processing of any energy (fat/glucose) that it can get it’s hands on. My minds eye sees the cell as a drowning person that’s gasping for air but can’t get any and flailing arms trying to grab onto anything to stay afloat.
      2. Pain as a rate limiter to prevent cellular damage while it waits on the energy processes to catch up. Only so much blood volume can pass by within a given time frame. Just like a car engine, if you start building it to make more and more power, but don’t provide enough fuel and the air/fuel ratio gets lean, the processes start breaking down and very bad things happen. The pain is a deterrent to continuing that activity to prevent a “lean” air/fuel condition.

      I’d love to see the insulin and triglyceride levels in that lean/obese/obese-diabetic chart since pre-diabetics (can you be obese and not be pre-diabetic/diabetic?) can have normal blood sugar levels. My guess is if the chart had these two metrics they would both be elevated as well in the obese/obese-diabetic because “insulin resistance”.

  5. and in their latest paper, Evanna Mills et al. works through the interaction of UCP1/BAT/ succinate/ thermogenesis and cold.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207988/

    “The newfound role for UCP1+ adipocytes as regulators of liver extracellular succinate also suggest that these cells can be leveraged to treat pathologies driven by chronic inflammation and fibrosis that depend on SUCNR1 signaling. Moreover, these discoveries provide a potential explanation for the longstanding observation that tissue extracellular succinate levels are substantial and dynamic. Tissue extracellular succinate concentrations are elevated in response to acute interventions like tissue hypoxia59, exercise60, and exposure to cold temperatures5. In the context of these acute physiological adaptations, succinate elevation is transient, and rapidly renormalizes. In contrast, in the setting of metabolic disease, circulating succinate levels are chronically elevated, a phenomenon which correlates with poor prognosis6–8. Therefore, a prediction of our findings here is that UCP1+ adipocyte content and activity will be linked to these adaptive and maladaptive processes by acting on extracellular pools of succinate. Taken together, our data therefore provide evidence for a major newfound physiological role for UCP1+ BAT and beige fat in regulation over liver extracellular succinate, independent of the historical view of these cells as regulators of whole-body energy expenditure and adiposity.”

  6. thought experiment- if successful use of succinate depends on effective UCP1 expression , then my first approach will be cyclic- banana milk shake with 25g of stearic acid for mitochondria fusion to see if we can get improved UCP1 , then follow with slow ramping up of succinate/ALA over a week.

  7. Due to nausea ….restarting low dose alpha lipoic acid 300 mg and soon to 600 and ultimately 1200mg if I can tolerate, then succinnade 7gm in divided doses/ day and hope for the best.

    Bass temps now about 97.4 to 97.7. However this not a real baseline as 1 yr of LA lowering and starting temp of more like 96.5.

    Currently eating more and weight gain but slow. If I was more careful I think it would not happen.

    Peak temps around 98.5

    Nightly Campari/ Jägermeister neat

    1. Yes, I’ve seen this paper about the role of succinate in cancer. Much of the paper is about how in many cancers you see a lack of succinate dehydrogenase (SDH) activity – just like in obesity. So succinate can build up in cancer cells due to lack of SDH activity. The approach of using ALA to deactylate SDH will hopefully turn it ON, the opposite of what is being seen in cancer cells.

      In some pathologies, you see a rise in circulating succinate. This is due to a global lack of SDH activity: no one can burn the succinate so they’re exporting it. The goal of ALA plus succinate is to get SDH working again and then feed it. We will know if this strategy works if our body temperature rises, our fasting blood glucose and lactate drop, etc. Furthermore, what we want to happen is to take the succinate into our cells and burn it, thus leading ultimately to LOWER circulating levels of succinate, as counter-intuitive as that might sound.

      The paper also mentions the potential pro-inflammatory effect of the succinate receptor (SUCNR1). I mentioned this in my article, but there are equal numbers of papers suggesting a anti-inflammatory role for succinate, so it’s hard to really characterize this. The paper about muscle fiber type switching from glycolytic to oxidative – like in lean people – suggests that SUCNR1 plays an important role in this seemingly beneficial transition.

      This leaves the question of HIF, which I don’t know enough about to comment on.

    2. Also worth pointing out. This is a Chinese paper published in a relatively minor journal. Sometimes there are great Chinese papers. Grain of salt, though.

  8. I had a headache for three days followed by nights of high heart rate and heavy sweating. Turns out my avg blood glucose has gone from 90-100s to 60-80s. While technically not hypoglycemic, I believe I am feeling those symptoms due to my previously higher than normal setpoint for all the associated signaling systems and regulatory subroutines.

    1. Wow, obviously those kinds of symptoms are not what you want. On the other hand, the drop in blood glucose is certainly suggestive that something is happening.

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