When Timing Matters - Alpha Lipoic Acid: Works Best, When it's Taken 30min Before a High Carb Meal. Can Easily Make You Hypo, if You Forget the Carbs or Have it on Empty

A salad like the one the beautiful young lady is about to eat is not the kind of meal that would require pre-meal lipoic acid supplementation.

Although I am not convinced that alpha lipoic acid (lipoic acid aka ALA) will actually partition glucose preferentially to muscle, because studies indicate that it will increase glucose uptake in fat cells, as well (and that at 10x higher glucose transporter expressions in fat vs. muscle cells; Estrada. 1996; Konrad. 2001), there is still good evidence that it can help people with (full-blown) insulin resistance stash away the glucose they consume, more effectively. To do so, it would appear logical that alpha lipoic acid has to be consumed in the vicinity of a meal.

The question I am trying to answer today is thus: When do you have to take your alpha lipoic acid to ensure optimal glucose "repartitioning"?

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The answer to this question - and I should not have to tell you that - will obviously depend on the pharmacokinetics of alpha lipoic acid. Pharmacokinetics, as they were observed in healthy, not in sick people.

Pharmacokinetics as they were described by Jens Teichert, Robert Hermann, Peter Ruus, and Rainer Preiss in a 2003 article in the Journal of Clinical Pharmacology (Teichert. 2003). In the corresponding experimental trial the plasma concentration-time courses, urinary excreted amounts, and pharmacokinetic parameters of alpha-lipoic acid metabolites were evaluated in 9 healthy volunteers after multiple once-daily oral administration of 600 mg racemic (=regular) alpha-lipoic acid.

"The primary metabolic pathways of alphalipoic acid in man, S-methylation and β-oxidation, were quantitatively confirmed by an HPLC-electrochemical assay newly established prior to the beginning of this study. Major circulating metabolites were the S-methylatedβ-oxidation products 4,6-bismethylthio-hexanoic acid and 2,4-bismethylthiobutanoic acid, whereas its conjugated forms accounted for the major portion excreted in urine." (Teichert. 2003)

The first important finding is that here was no statistically significant difference in the pharmacokinetic parameters Cmax, AUC, and t_max between day 1 and day 4. That's relevant because it means that any prescription we develop based on the results will remain valid for one week, one month and probably the rest of your life.

No, there is no evidence that R-ALA is better than regular ALA: While there is one study showing that a high dose of S-ALA, the second of two isomeres you will find in regular ALA supplements will not increase the glucose uptake into insulin resistant muscle cells in the petri dish (Streeper. 1997), there is no study as of yet that would prove the superiority of R-ALA over racemic mixtures of both R-ALA and S-ALA in human beings. And effects such as those described by Streeper et al. for R-ALA have also been observed for regular ALA dozens of times (Jacob. 1996; Khamaisi. 1997; Weinstein. 2001).

Moreover, despite the prolonged half-lives of the major metabolites compared to the parent drug, no evidence of accumulation was found. Unlike creatine, for example, alpha lipoic acid can thus not be cycled. It has to be taken continuously.

Illustration 1: At least after only four days on ALA its pharmacology in healthy human subjects doesn't change significantly - taking it 30 min before a meal thus appears to be a valid strategy even for chronic use (Teichert. 2003)

The data the scientists collected also indicate that the major pathway through which ALA is elminates is not, as you may expect urinary excretion. In the study at hand, only 12.4% of the administered dose were recovered in the urine after 24 hours as the sum of alpha-lipoic acid and its metabolites. As Teichert et al. point out,...

"[t]he results of the present study revealed that urinary excretion of alpha-lipoic acid and five of its main metabolites does not play a significant role in the elimination of alpha-lipoic acid."

This does also imply that biliary excretion, further electrochemically inactive degradation products, and complete utilization of alpha-lipoic acid as a primary substrate in the endogenous metabolism are more likely candidates for the primary pathways of excretion.

Do you remember? ALA has only recently been shown to normalize the high fat diet induced synchronization issues of the internal clocks in rodents (learn more). Interestingly, this was achieved without having to time the ingestion of ALA by simply adding 0.2% lipoic acid to their diets. Against that background it is unlikely that "untimely" supplementation will, as it was the case for meltonin (learn more) - mess with the circadian rhythm. The issue of potential hypoglycemic episodes, on the other hand, is very real and should not be taken lightly - specifically by those of you who don't belong to the ever-increasing (still) minority of insulin-resistant (pre-)diabetics.

What's really relevant is yet not how alpha lipoic acid leaves your body, but rather the time it takes for the serum levels to peak. A time-span, Teichert et al. quantify as ~30 minutes. A value that is in line with the timing a group of German scientists used in the first (and AFAIK only) human study that produced results that would warrant the hype surrounding the use of alpha lipoic acid as insulin sensitizers (Jacob. 1999).

Figure 1: Increase in insulin-stimulated glucose disposal according to treatment (Jacob. 1999)

In said study seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) α-lipoic acid.

By the means of an isoglycemic glucose-clamp the authors of the study were able to confirm the results of a previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA.

The data in Figure 1 (bottom) does yet also tell you that the alpha lipoic treatment did not work for all of the seventy four-patients; and interestingly, the efficacy didn't depend on the amount of the of ALA that was used - more is thus, once again, not necessarily better.

The same timing was used in a 2011 study by Koh et al. who conducted a randomized, double-blind, placebo-controlled, 20-week trial, 360 obese individuals with 1200 or 1800 mg/d of alpha-lipoic acid or placebo.

Figure 2: Changes in Body weight over the course of the 20-week study (Koh. 2011)

Due to the longer duration of the study the scientists were also able to determine the one thing everyone is interested it: weight loss! As you can see in Figure 2, the subjects in the high dose alpha lipoic acid group lost a significant amount of weight, regardless of the fact that they were not even dieting. Needless to say that you cannot expect similar results if you are not obese and diabetic, but if you are significantly overweight or (pre-)diabetic, the Koh study provides a strong incentive to go and buy a bottle of 600mg ALA tablets.

Figure 3: ALA can trigger hypoglycemic episodes, because it blunts gluconeogenesis in the liver (Khamaisi. 1999)

Timing matter for non-diabetics, as well: And even if you are neither one, nor the other, timing matters. Taking alpha lipoic acid before a workout to increase AMPK and hope for increases in fatty acid oxidation is only going to increase your risk of going hypoglycemic (with all its recently discussed potentially obesogenic negative side effects). Similar effects can be expected if you've been fasting, then pop a couple of ALA pills and wait another 1-2h before you're finally giving your body what it will be craving for: sugar.

You think that's just biased bullshit? Well, take a parting look at the data in figure 3. Do you really want to be that normoglycemic guy who ends up in acute hypoglycemia because ALA increased his cellular glucose uptake and inhibited gluconeogenesis, i.e. the production of glucose from fat and/or amino acids in the liver, to an extend that left him hypo?

I don't think so. And I am pretty sure, the ravenous cravings and low energy levels you may be experiencing during and after these episodes are not going to help you achieve the perfect physique you may be thriving for | Comment on Facebook!

References:

• Estrada, D. Elizabeth, et al. "Stimulation of glucose uptake by the natural coenzyme α-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway." Diabetes 45.12 (1996): 1798-1804. 
• Jacob, Stephan, et al. "The antioxidant α-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle." Diabetes 45.8 (1996): 1024-1029.
• Jacob, S., et al. "Oral administration of rac-α-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial." Free Radical Biology and Medicine 27.3 (1999): 309-314. 
• Khamaisi, Mogher, et al. "Lipoic acid reduces glycemia and increases muscle GLUT4 content in streptozotocin-diabetic rats." Metabolism 46.7 (1997): 763-768.
• Khamaisi, Mogher, et al. "Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats." Metabolism 48.4 (1999): 504-510.
• Koh, Eun Hee, et al. "Effects of alpha-lipoic acid on body weight in obese subjects." The American journal of medicine 124.1 (2011): 85-e1. 
• Konrad, Daniel, et al. "The Antihyperglycemic Drug α-Lipoic Acid Stimulates Glucose Uptake via Both GLUT4 Translocation and GLUT4 Activation Potential Role of p38 Mitogen-Activated Protein Kinase in GLUT4 Activation." Diabetes 50.6 (2001): 1464-1471. 
• Streeper, Ryan S., et al. "Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle." American Journal of Physiology-Endocrinology And Metabolism 273.1 (1997): E185-E191.
• Teichert, Jens, et al. "Plasma kinetics, metabolism, and urinary excretion of alpha‐lipoic acid following oral administration in healthy volunteers." The Journal of Clinical Pharmacology 43.11 (2003): 1257-1267. 
• Weinstein, Randi B., Hans J. Tritschler, and Erik J. Henriksen. "Antioxidant alpha-lipoic acid and protein turnover in insulin-resistant rat muscle." Free Radical Biology and Medicine 30.4 (2001): 383-388.

Circadian Clock Normalization as Novel Mechanism Behind the Health Benefits of ALA in NAFLD & Diabesity | Plus: ALA For Athletes & the Obese - Yes/No + When to Take It?

Yes, you can buy alpha lipoic acid as bulk powder, but if you still have intact mucosa and want to keep it intact, I suggest you swallow pills.

Alpha lipoic acid aka "ALA" is a natural AMPK agonist that works similar to metformin. Developed by BASF and others as an anti-diabetes medication in the late 20th century, it's now a popular supplement that is prescribed as a "drug" to type II diabetics only rarely and only in Europe, yer not in the US.

Based on the currently available evidence its anti-diabetic effects are comparable, but far inferior to metformin. In view of the fact that lipoic acid is also non-patentable and thus not exactly profitable, it's no wonder that it has disappeared from the radar of the medical establishment over the past decade.

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A recent study from the Linus Pauling Institute may yet well put the naturally occuring power-antioxidant, which is found at higher levels in organ meats and leafy vegetables such as spinach and broccoli, back onto the research agenda of top scientists all around the world.

Lipoic acid  appears to reset and synchronize circadian rhythms, or the "biological clock" found in most life forms. The ability of lipoic acid to help restore a more normal circadian rhythm to aging animals could explain its apparent value in so many important biological functions, ranging from stress resistance to cardiac function, hormonal balance, muscle performance, glucose metabolism and the aging process.

Figure 1: ALA had no direct weight loss effect, but it reduced the abnormal cortisol excursions and the increase in postprandial fatty acid synthesis in the old rodents (Keith. 2014)

The findings were made by biochemists from the Linus Pauling Institute at Oregon State University, and published in Biochemical and Biophysical Research Communications, a professional journal.

"This could be a breakthrough in our understanding of why lipoic acid is so important and how it functions. Circadian rhythms are day-night cycles that affect the daily ebb and flow of critical biological processes. The more we improve our understanding of them, the more we find them involved in so many aspects of life, "said Tory Hagen, the Helen P. Rumbel Professor for Healthy Aging Research in the Linus Pauling Institute, and a professor of biochemistry and biophysics in the OSU College of Science

Almost one-third of all genes are influenced by circadian rhythms, and when out of balance they can play roles in cancer, heart disease, inflammation, hormonal imbalance and many other areas, the OSU researchers said. Of particular importance is the dysfunction of circadian rhythms with age.

"In old animals, including elderly humans, it's well-known that circadian rhythms break down and certain enzymes don't function as efficiently, or as well as they should," said Dove Keith, a research associate in the Linus Pauling Institute and lead author on this study.

If lipoic acid offers a way to help synchronize and restore circadian rhythms, this could be a quite significant result. In that it is yet important to know if the effects, the researchers observed only in the liver, are mediated by effects that are independent of the anti-oxidant effects of lipoic acid - or, to put it differently, if lipoic acid has direct or just indirect effects which are mediated by the blockade of pro-oxidant disturbances of the "circadian clock" of the liver.

Figure 2: AMPK expression in white & brown fat and muscle (top, based on Prieto-Honta. 2012), and implications (bottom)

I guess it would be pretty unsatisfying if I passed on this opportunity to review a handful of recent studies on the benefits of alpha lipoic acid, right? Well, then... I guess you will remember that I am skeptical about it's usefulness as a nutrient partitioner, right? Although we have only rodent data to support this hypothesis the increase in AMPK expression that would come at a very unfavorable moment, if you take your "repartioning supplement" shortly before or with a meal did after all leave the rodents in the previously discussed study by Prieto-Hontoria et al (2012) lighter and less muscular (see Figure 2, as well as previous article "Lean & Muscular W/ Alpha Lipoic Acid? You Could Be Just as Lean, But More Muscular W/out "Nutrient Repartitioner"!" | read more).

That obviously doesn't mean that ALA was useless. In a different scenario - e.g. for someone with a high(er) baseline inflammation - alpha lipoic acid may well have beneficial "nutrient repartitioning effects". Examples? What about the seminal paper by Ko et al. (2011)?

In said study, 360 obese individuals (body mass index [BMI] ≥30 kg/m2 or BMI 27-30 kg/m2 plus hypertension, diabetes mellitus, or hypercholesterolemia) were randomized to alpha-lipoic acid 1200 or 1800 mg/d or placebo. The supplement was consumed in three doses of 600mg timed 30 minutes before a meal. Now in my past articles I have often pointed out that supplement timing may be overrated. In the case of ALA it does yet make perfect sense for diabetics and insulin resistant obese people (!) to take it before a meal, in order to benefit from the insulin sensitizing effects of the AMPK activator alpha lipoic acid.

Figure 3: Weight loss during 4-week induction and 16-week follow up in the placebo, 1,200mg and 1,800mg ALA groups (left) and relative weight loss at the end of the study in all "completers" (Koh. 2011)

As you can see in Figure 3, the timely use of 600mg of alpha lipoic acid before each of the meals lead to significantly increased weight loss, specifically in the latter phase of the 20 week trial, in the course of which the subjects had to consume 600kcal less - but at least 1,200kcal/day - than their habitual diet would provide. Quite an impressive result of which the researchers from the University of Ulsan College of Medicine in Seoul say that its efficacy and safety (compared to other anti-obesity drugs) would "suggest that alpha-lipoic acid may be effective as an adjunctive medication for obesity" (Koh. 2011) - a medication, and you can see that in Figure 3, that helps with both: weight and fat loss!

Whether ALA is or isn't for hard-training athletes / gymrats remains to be seen

Unfortunately, studies on athlete subjects are quasi non-existent. What we know is that alpha-lipoic acid can be used to increase the accumulation of creatine in the muscle (learn more | baking soda is probably more effective, though) and that it diminishes the exercise induced oxidative damage without having significant beneficial (or negative) effects on exercise performance in the short run (Zembron-Lacny. 2009).

ALA or R-ALA? There is no reliable evidence that R-ALA would produce superior effects in in vivo studies. The often cited study by Streeper et al. (1997), for example, was conducted on isolated, insulin resistant rat muscle in the Petri dish and is thus hardly representative of trained athletes. In fact, the vast majority of studies reporting metabolic benefits from the use of alpha lipoic acid used the racemic mixture of the R- and the allegedly "toxic" S- isomer of alpha lipoic acid. If you still insist on R-ALA make sure it's bound to sodium (Na), because the unbound version won't even make it into your blood-stream (Carlson. 2007).

Otherwise you will find patent after patent with hilarious, scientifically unverified claims about "muscle building", "body recompositioning" and "performance enhancing" effects of ALA in athletes.

Reliable evidence that any of these effects exist in athletes who follow a clean, whole foods based high(er) protein diet, however, is absent. If anything, one could cite a relatively exotic rodent study that was published in the Journal of Shaanxi Normal University (Natural Science Edition) in 2006. In said study, the Chinese scientists observed a glycogen preserving effect of ALA in rats who were trained to exhaustion (Xiong. 2006). Whether or not these or other benefits outweigh a potentially reduced adaptive response to exercise as it was observed for n-acetyl-cystein (NAC) by Michailidis et al. in 2013 remains questionable, though.

Figure 3: Highly significant increases in PPAR-alpha are partly responsible for the reduced hepatic fatty liver synthesis and should help prevent NALD (Keith. 2014)

Let's get back to the "clock issue": It remains to be seen if similar effects on the clock genes in the liver can be observed in older humans, as they have now been reported for rodents with the standard 600mg/day servings of alpha lipoic acid of which previous studies show that it can help with diabetes and non-alcoholic fatty liver disease.

Until we don't know the exact mechanism by which alpha lipoic acid works its restorative magic on the clock genes of your liver, we cannot tell if it has to be timed appropriately, either. For melatonin, which is a cyclically produced hormone correct timing is a must. For lipoic acid it's probably irrelevant... at least if its effects are in fact mediated by the powerful antioxidant effects of lipoic acid | Comment!

References:

• Carlson, David A., et al. "The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects." Alternative Medicine Review 12.4 (2007): 343.
• Dove Keith, Liam Finlay, Judy Butler, Luis Gómez, Eric Smith, Régis Moreau, Tory Hagen. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age. Biochemical and Biophysical Research Communications, 2014
• Koh, Eun Hee, et al. "Effects of alpha-lipoic acid on body weight in obese subjects." The American journal of medicine 124.1 (2011): 85-e1.
• Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Martínez JA, Moreno-Aliaga MJ. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr. 2012 Jun 5. [Epub ahead of print]
• Streeper, Ryan S., et al. "Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle." American Journal of Physiology-Endocrinology And Metabolism 273.1 (1997): E185-E191.
• Xiong, Zheng-ying, and Hai-bin LIU. "Effects of alpha-lipoic acid on glucose reserve and moving capacity of training rats [J]." 
• Zembron-Lacny, A., et al. "Assessment of the antioxidant effectiveness of alpha-lipoic acid in healthy men exposed to muscle-damaging exercise." J Physiol Pharmacol 60.2 (2009): 139-43.