Sunday, October 12, 2014

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!
  • 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.