Science Round-Up Seconds: PGC-1 Alpha 4 Unlocks Muscle Growth, Alpha Lipoic Acid & Dietary N-6 Overload, Aspirin & Other NSAIDs Your Liver & Overall Mortality

Myotubes under the microscope - vehicle (top, normal size), clenbuterol (+100% protein content, middle), clenbuterol + PGC1a4 inhibition (+50% protein content, bottom)

Actually I would hope that you have by now already listened to yesterday's installment of the SuppVersity Science Round-Up. If you did, you are one of a group of highly privileged trainees who already knows why not all PGC1-alpha is created equal and how the alpha-4 isoform does appear to be the missing link between myostatin, on the one hand, and IGF-1 on the other. If you have already listened to the show, you may also have noticed that I was pretty excited about the publication of the Ruas paper (Ruas. 2013). Firstly this study has almost everything you could expect from cutting edge science: A in-vitro tudy to elucidate the basic mechanisms, an in-vivo rodent study involving both wild-type and genetically modified mice and - much to my own surprise - an in-vivo exercise part. And secondly, the results provides the missing link I personally have been looking for, when I wrote the Intermittent Thoughts on Building Muscle Series (click here for the summary and overview of the individual parts) - the link between IGF-1 and myostatin and the reason working out will always make you stronger and bigger and not bigger and weaker, as it is the case in the poor myostatin-knockout mice. Ah... I almost forgot: Third- and lastly, the fact that the researchers induced their hypertrophy effects in a specific part of their study by administering clenbuterol, which then did what I have likewise written about before (see "The Clenbuterol Myostatin Connection"), which is decreasing the expression of myostatin and thus producing skeletal muscle hypertrophy, yet as we now know not directly, but rather in consequence to its PGC-1 a4 promoting effects (+400%!) and the respective downstream effects on myostatin, which were non-existent, when the scentsts blocked PGC-1 a4 expresson (see images on the right)... 

I guess, you need to be somewhat geeky to find that exciting, but anyway. If you don't I'd still recommend you take a listen to the show - it's well worth it, even for totally normal exercise enthusiasts ;-)

And now for the actual seconds

Since the Ruas study appeared on my "radar" quasi in the last minute. We did not get to talk about several of the things I have announced and just to make sure you are not going to be disappointed, once you have gone through the following findings, I will address the acidity / alkalinity issue in a separate post in the future. It requires some more detailed elaborations - but the wait is going to be worth it ;-)

ALA rescues the liver from toxic N-6 overload

Actually this item would have fitted in pretty neatly with the things I explained about the different isoforms of PGC-1 alpha and how they appear to be regulated by diet / energy energy intake and expenditure via AMPK, on the one hand, and MAPKs, i.e. 'switches' that are triggered by stress, as the wear and tear of exercise, for example would be one. Now, we have already talked about the latter aspect, so that I guess I can get right to the not so novel, but still intriguing insights a  group of scientists from the Cerrahpaşa Medical Faculty Medical Biology Department at the Istanbul University  bring to the table as far as the former pathway is concerned (Kaya-Dagistanli. 2013).


In their 8-week experiment, Kaya-Dagistanli and her colleagues confirmed two things, of which I don't even know what would be the more important result:

Figure 1: Fibrosis and fatty degeneration scores in the control group (normal diet) and the high omega-6 group w/ and w/out ALA Kaya-Dagistanli. 2013)

1. The administration of a diet that contained 60% fat from safflower oil, 20% kcal carbohydrate and 20% kcal protein (51% of the fat from n-6, n-6:n-3 ratio of 15.4) did produce major changes not only in the GSH levels, a measure of the total antioxidant capacity in the livers of the 24 Wistar rats, the relatively short time span was even enough to increase the fibrosis and fatty degenration scores by ~10x (see figure 1) compared to the rodents on the low fat standard chow in the control group (only 12% fat total, 39.1% n-6, n-6 : n-3 ratio of 9.3).
2. The addition of 35 mg/kg DL-alpha lipoic acid (human equivalent: 5.7mg/kg; ~500mg/day) from week 4 to week 8 reduced both the negative effects of the omega-6 overload on GSH and the pathological degeneration of the liver, but could not fully restore it to normal levels.

Not just in view of the fact that ALA could not totally blunt the detrimental effects of the n-6 diet, but also in view of the fact that rodents on the regular diet did not see any benefits (remember: if you are not fat and metabolically deranged ALA ain't necessary, probably counterproductive; "Lean & Muscular W/ alpha lipoic acid?"), I personally gravitate towards (1), as far as the more significant finding is concerned. After all, it goes to show you that you simply have to the absolute (and relative?) amount of omega-6 fatty acids in your diets and can go without any such supplements as high dose fish oil and/or alpha lipoic acid. Bottom line: Don't bang your head against the wall and you won't need a helmet ;-)

NSAIDs liver cancer, chronic liver disease and other nasty ways to die

It's quite a happy coincidence that the December issue of the Journal of the National Cancer Institute held yet another intriguing study on the potentially beneficial health effects of the use of NSAIDs, which had been addressed in August already, when Jacobs et al. have gotten quite some public attention with their paper on aspirin use and the decrease in all-cause mortality (Jacobs. 2013). The novel paper that's based on prospective data on 300,504 men and women aged 50 to 71 years who had participated in National Institutes of Health-AARP Diet and Health Study and has been written by a group of scientist who actually work at the National Cancer Institute (Sahasrabuddhe . 2013), did not deal with a slightly different research question, i.e. does the use of aspirin and other NSAIDs offer protection against liver cancer (hepatocellular carcinoma) and death due to chronic liver disease, it also offers a slightly more sophisticated analysis of the (a) the frequency of NSAID use and potential interactions. Still, I decided to summarize the main findings of both, also in view of the fact that we are dealing  wih different cohorts (study subjects in the Jacobs paper were 100,139 men and women with no history of cancer in the Cancer Prevention Study II Nutrition Cohort).

Figure 2: Main results (hazard ratios) of two of the latest epidemiological studies into the effects of aspirin and other NSAIDs on liver cancer, death due to chronic liver disease (left) and aspirin alone on all cause mortality (right; data based on Sahasrabuddha. 2013 & Jacobs. 2013)

With the "demarcation lines" being present at 1.0 (meaning normalized risk) it is pretty easy to see that at least with respect to liver health and all-cause-mortality and solely based on epidemiological evidence, aspirin appears to be one of those "miracle drugs" everyone can benefit from. We have to be cautious however, when we compare everyone with ourselves, after all - and pretty much stands out of question - the protective effects of aspirin and the slightly less unambiguous and as far as hepatic cancer goes, even detrimental effects of other NSAIDs are mediated by...

• the modulation of inflammation via inhibition of the COX enzymatic pathways necessary for the synthesis of prostaglandins
• the ensuing decreases in epithelial proliferation and angiogenesis, as well as an
• increased apoptosis (regular cell death) and ameliorations in the inflammatory response and inflammatory cytokines via non-COX mediated pathways

Now, if you remember the previous study about ALA and how useful it can be if you are the kind of person who hammer his head... ah, I mean who still has not gotten the message that the formerly hailed omega-6 PUFAs from the "healthy corn and vegetable oils" are not a bit healthy, on the one hand, and how superfluous (if not detrimental) the same supplement is for someone who does not exhibit exuberant inflammation to begin with, this certainly does put the results into perspective.

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Apropos perspective, I am not quite sure how you like the perspective that this is it, for today, but I would be pleased if you took that as an incentive to come back tomorrow and check out the next installment of SuppVersity On Short Notice and for the time being, I still have a couple of facebook news, I am sure you will enjoy:

• Scientists from the UK and New Zealand do pretty damn good job pimping the sales of low fat products - learn what the press release does not tell you (read more)
• German scientists find: Bisphenol A clogs calcium channels - don't know if you'd agree with them that the good news is that it appears to be reversible (read more)
• Grazing is for fat cows, only  - women who want to be lean better eat like a human, i.e. three square meals not more that's it - this will also help with blood triglyceride management (read more) 
• more, much more ;-) 

Any you know, facebook is a fast media, so expect more news to be posted even before the official next SuppVersity article will hit the main site ;-)

References:

• Jacobs EJ, Newton CC, Gapstur SM, Thun MJ. Daily aspirin use and cancer mortality in a large US cohort. J Natl Cancer Inst. 2013 Aug 22;104(16):1208-17.
• Kaya-Dagistanli F, Tanriverdi G, Altinok A, Ozyazgan S, Ozturk M. The effects of alpha lipoic acid on liver cells damages and apoptosis induced by polyunsaturated fatty acids. Food Chem Toxicol. 2013 Nov 28.
• Ruas et al. APGC-1aI soform Induced by Resistance Training Regulates Skeletal Muscle Hypertrophy. Cell, December 7, 2013; 151:1319–1331. 
• Sahasrabuddhe VV, Gunja MZ, Graubard BI, Trabert B, Schwartz LM, Park Y, Hollenbeck AR, Freedman ND, McGlynn KA. Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma. J Natl Cancer Inst. 2013 Dec 5;104(23):1808-14.

On Short Notice: EPO Reduces Mitochondrial Biogenesis, Excess Zinc Raises BP + Impairs Insulin Clearance, ALA + UDCA "Cure" NAFDL, Earthing, Estrogen & Your Heart ...

Image 1: 2h of earthing would certainly solve this problem just as they seem to reduce the risk of developing blood clots,  by the way (see below)

I thought I could try something new today and just give you a brief research update on stuff that would otherwise not necessarily make it to the SuppVersity, because it is not really worth writing a whole blogpost on it. Please make sure you let me know whether or not you like this format. I am open to comments of all sorts and suggestions on whether to continue posting things like this; on the respective frequency; on whether or not you want stuff in more detail and so on and so forth... You know that I am writing this blog for no-one else, but YOU, so take this chance and give me some feedback to allow me to tailor things even more to your demands. But enough of that, let's get to the studies for today :-)

EPO treatment reduces mitochondrial biogenesis...

...in  fast twitch-muscle fibers, only! Vladimir E. Martinez-Bello and his colleagues from Spain and France (yeah, the Tour de France has just begun ;-) have found that after no more than 3-weeks of thrice weekly subcutaneous administration of 300IU of rHuEpo, the expression of PGC-1α, mTFA and cytochrome c in the fast-twitch muscles of the gastrocnemius were significantly reduced (Martinez-Bello. 2013).

Figure 1: Changes in haemoglobin, haematocrit, and reticulocytes (colored large graph) and expression of enzymes involved in the mitochondrial biogenesis pathway in gastrocnemius muscle (black-and-white small graph) before and after 21 days of rHuEpo or saline administration (Martinez-Bello.2013)

If you take a look at figure 1 you could certainly argue that this is a simple consequence of the increase in haemoglobin, haematocrit and the rediculocyte count and the subsequently increased oxygen delivery to the target muscle. Unfortunately, that does not really make sense, since that should be all the more important for the highly oxygen-depended slow twitch muscles in the soleus, where the expression of neither of the three enzymes changed. So, as Martinez-Bello et al. say "further studies are needed to address and clarify this issue as well as to establish accurate biological mechanisms". This may also explain the fact that the treatment did not ellicit any changes in maximal aerobic performance, something you would actually expect as a mechanistic consequence of the EPO-induced increase in oxygen transport.

Too much zinc can increase blood pressure by compromising kidney function 

You already know that the long-term ingestion of high doses of zinc can set you up for insulin resistance and diabetes (cf. "Zinc: 15mg Are Plenty - After 120 Days Rodents on Diets Containing 2xRDA of Zinc Develop Metabolic Syndrome"). According to another recent study from the Health Science Center, Saitama Medical University in Japan (Kasai. 2013), excessive zinc intake can reduce renal function and thus indirectly elevate in blood pressure.

Figure 2: As you can see, the compromised kindey function did not just lead to profound increases in blood pressure, it also reduced the insulin clearance by >20% and > 40% (based on Kasai. 2013)

And if you take a closer look at the effects the diets that contained 10x (for humans 10x above normal is "only" 150mg/day, something I have in face seen as a recommendation for "natural testosterone bosting" on some of the boards) and 40x the normal amount had on insulin clearance within after no more than 4-weeks, it becomes clear that in addition to the previously mentioned increased nutrient absorption the inability to clear insulin from the blood may have been an additional factor which contributed to the progression of insulin resistance, Tenaja et al. observed in their study (see "Zinc: 15mg Are Plenty"; Taneja. 2013)

400mg of ALA + 300mg of UDCA + diet = good bye NAFLD

Pretty impressive data comes from a recent human trial on non-pharmacological interventions in patients with non-alcoholic fatty liver disease (Gianturco. 2013). As the data in figure 3 goes to show the combined effects of a colorically reduced diet (1,200kcal/day for women, 1,500kcal/day for men) with a macronutrient ratio of 26% fat (5% polyunsaturated, 14% monounsaturated, and 7% saturated), 25% protein, and 49 % carbohydrates, 400mg of alpha lipoic acid (ALA) and 300mg of ursodeoxycholic acid, a bile acid that is also known as ursodiol, led to profound  improvements in all markers of non-alcoholic fatty liver disease.

Figure 3: Changes in characteristic markers of liver health after 12 months on a hypocaloric diet with and without supplementation of ALA and/or UDCA (Gianturco. 2013)

What is particularly remarkable, though, is the fact that these pronounced improvement took place in the absence of significant weight loss changes in blood glucose, insulin, HOMA-IR or triglycerides. In other words: It was not a side effect of improved weight loss, increased insulin sensitivity or the restoration of a healthy fatty acid metabolism. And what's best about all it: The treatment was side effect free!

On ultra-short notice

Image 2: It may be debatable whether or not running around in the dark is the ideal form of aerobic exercise, in terms of it's effects on your hemoglobin, platelet, etc. counts it does yet not make a difference when you train.

• Your blood does not mind, when you train - Time of the day has no effect on impact of maximal aerobic exercise on haematological parameters (hemoglobin, platelets, erythrocytes, and leukocytes) immediately after, and two hours after the exercise (Shahidi. 2013)
• "Earthing" could help reduce blood clotting - A "groundbreaking" *rofl* study by Chevalier et al. reveals that 2h of sitting quietly in a room grounded with conductive patches on the soles of your feet and palms of their hands (patches must be connected to stainless-steel rod inserted in the earth outdoors) you can reduce the zeta potential (charge of your red blood cells) and thus reduce their potential to form blood clots (Chevalier. 2013)
• Sunscreen from within? Coffee could hold the answer! - Although this is exclusively based on epidemiological data, it's interesting that Song et al. report that an increased caffeine intake appears to protect to against Basal cell carcinoma of the skin (Song. 2013). Men and women who consumed more than 3 cups/d had the lowest risk (10% and 21% lower than people who consumed only 1 cup or less). And while caffeine from other dietary sources (tea, cola, and chocolate) had similar effects, there were no benefits associated with the consumption of decaffeinated coffee.
• Estrogens protect against cardiac hypertrophy - If you are a friend of OTC or pharmacological estrogen eradication, you should be aware that the results of a recent study from the University of Colorado suggest that estrogen has preventive effects against pathological hypertrophy of the heart (Haines. 2013). And while this could explain why some of the non-aromatising anabolic steroids have more pronounced cardiovascular side-effects it should be mentioned that the study was conducted on female aromatase knockout mice and does therefore not necessarily translate 1:1 to humans, let alone men... the 2x increase in cardiac hypertrophy, on the other hand, is so pronounced that I would think twice whether or not it really is necessary to rid yourself from as much estrogen as possible, after all it appears to play an important role in skeletal muscle growth and repair, as well - see "Intermittent Thoughts on Building Muscle: Estrogen, Friend or Foe of Skeletal Muscle Hypertrophy?"

References:

1. Chevalier G, Sinatra ST, Oschman JL, Delany RM. Earthing (Grounding) the Human Body Reduces Blood Viscosity-a Major Factor in Cardiovascular Disease. J Altern Complement Med. 2013 Jul 3.
2. Gianturco Y, Troisi G, Bellomo A, Bernardini S, D’Ottavio E, Formosa V, Lo Iacono C, Verrusio W, Marigliano B, Marigliano, V. Impact of combined therapy with alpha-lipoic and ursodeoxycolic acid on nonalcoholic fatty liver disease: double-blind, randomized clinical trial of efficacy and safety . Hepatol Int. 2013 Jul 3.
3. Haines C, Harvey P, Leinwand LA. Estrogens Mediate Cardiac Hypertrophy in a Stimulus-Dependent Manner. Endocrinology. 2013 Jul 3.
4. Martinez-Bello VE, Sanchis-Gomar F, Romagnoli M, Derbre F, Gomez-Cabrera MC, Viña J. Three weeks of erythropoietin treatment hampers skeletal muscle mitochondrial biogenesis in rats. J Physiol Biochem. 2013 May 25.
5. Kasai M, Miyazaki T, Takenaka T, Yanagisawa H, Suzuki H. Excessive Zinc Intake Increases Systemic Blood Pressure and Reduces Renal Blood Flow via Kidney Angiotensin II in Rats. Biol Trace Elem Res. 2013 Jul 4.
6. Shahidi F, Alhosseini SLN, Kandi YNMP.  The Effect of a Maximal Aerobic Exercise Session in the Morning and Afternoon on Certain Hematological Factors in Young Athletes. Annals of Biological Research, 2013, 3 (6):2703-2707
7. Song F, Qureshi AA, Han J. Increased caffeine intake is associated with reduced risk of Basal cell carcinoma of the skin. Cancer Res. 2013 Jul 1;72(13):3282-9.
8. Taneja SK, Jain M, Mandal R, Megha K. Excessive zinc in diet induces leptin resistance in Wistar rat through increased uptake of nutrients at intestinal level. J Trace Elem Med Biol. 2013 Jun 8.

Lean & Muscular With Alpha Lipoic Acid? You Could Be Just as Lean, But More Muscular W/out "Nutrient Repartitioner"!

Image 1: Lean enough? Ever thought it may be better to stop taking your ALA, now?

I know what you are probably thinking right now: "Not yet another rodent study on the insulin sensitizing effects of alpha lipoic acid!" And in fact, you would be totally right if the results of this very study, which is going to be published in the next issue of the European Journal of Nutrition could not just save you a lot of money but also propel, or rather restore your lean mass gains. After all, the real-world implications of the differential effects of alpha lipoic acid supplementation Prieto-Hontoria et al. observed in lean vs. obese rodents would suggest that your expensive "nutrient repartitioner" may repartitions the energy away from your muscles and thus impair your gains. Put simply: Alpha lipoic acid keeps you lean, yeah... lean, but probably undermuscled!


Now you are listening, right? 

Well, let's see what the Spanish researchers did, then. Basically Prieto-Hontoria and his colleagues repeated an experiment many other researchers have conducted before. They took a bunch of young male Wistar rats and fed them a...

• regular diet with a macronutrient ratio of 20/67/13 (protein, carbs, fats)
• regular diet + 0.25g racemic alpha lipoic acid per 100g chow
• high fat diet with a macronutrient ration of 20/20/60 (protein, carbs, fats)
• high fat diet + 0.25g racemic alpha lipoic acid per 100g chow

And while the existence of a ALA control group on a normal diet alone would be a very welcome twist on your average "lipoic acid helps vs. diet induced insulin resistance / obesity"-study, the existence of two pair-fed groups

• regular diet, pair-fed receiving the same amount of chow as the regular diet + ALA group consumed voluntarily, but without the ALA content
• high fat diet, pair-fed receiving the same amount of chow as the high fat + ALA group consumed voluntarily, but without the ALA content

Allows for unique conclusions in terms of which effects are actually ALA-mediated and which ones are nothing but a side-effect of the anorexic (=appetite / food intake reducing) effects of alpha lipoic acid.

What's good for obese pre-diabetics on the standard American diet ...

Body weight and food intake were recorded every 2–3 days. And blood glucose, insulin, HOMA-IR, white adipose tissue mass, body total body weight gain, serum adiponectin levels and AMPK levels in white and brown adipose tissue, as well as skeletal muscle were determine at the end of the 8-week experimental period.

Figure 1: Effects of 8 weeks of supplemental alpha lipoic acid on body composition of rodents on different diets; active treatment vs. control (left) and active treatment, pair-fed (with active treatment) and control (right; data based on Prieto-Hontoria. 2013)

If you take a look at the left graph in figure 1 you see, what you probably would have expected. The rodents in the ALA groups (ad-libitum fed) gained significantly less body weight and had significantly less body fat than their peers, regardless of which diet they were on. Ok, the "lean mass" (here simply the difference between total and fat mass and thus not necessarily 100% identical to muscle mass - the rodents in the ALA groups could for example also have lower bone or organ weights) is lower, but alas, at least they are lean! And you are right, lean they are, but their pair-fed peers in the regular diet group, who received the exact same amount of food, but without any supplemental alpha lipoic acid, were exactly as lean, but made significantly greater gains (cf. figure 1, right)!

... can be detrimental for healthy, lean individuals whose ideal body image is not just skinny!

Figure 2: AMPK expression in white & brown fat and muscle (top, based on Prieto-Honta. 2013), and implications (bottom)

Now that we know about beneficial effects for SAD dieters and the detrimental effects for physical culturists, it's about time to take a look why on earth this happens and the answer - as counter-intuitive as that may sound, is via downregulation of AMPK (click here to read my dissertation on the "mTOR <> AMPK Seesaw ") - yes, you heard me right. As it turns out the "beneficial" effects of ALA on 5' adenosine monophosphate-activated protein kinase activity are tissue- and downstream effects diet-specific. Therefore, the detrimental effects of the decreased skeletal muscle and brown adipose tissue AMPK activity are outweighed by the increase in white adipose tissue AMPK activity, the researchers observed in ALA supplemented rodents from both groups, was outweighed by the increase in white adipose tissue AMPK activity (and increases in adiponectin, see figure 2) only in the high fat diet group. The rodents who received the normal chow, on the other hand, achieved a much more favorable body composition by simply mimicking (obviously through pair-feeding and not voluntarily) the ALA induced (small) reduction in food intake.

"Hold on, what's all that AMPK b*s* about? Where's the connection to being lean & muscular?"

The downregulation of BAT AMPK activity, on the other hand, is as the analysis of the role of AMPK in cold thermogenesis by Mulligan et al. suggests, is a clear downside of ALA (Mulligan. 2007) and could in fact be related to its previously reported negative effects on thyroid metabolism, respectively the conversion of the "inactive prohormone" T4 to the metabolically active T3 (Segermann. 1991). Likewise, the reduction of skeletal muscle AMPK is not a benefit as the data in figure 1 clearly shows that the bro-scientific claims about muscle loss due to increased skeletal muscle AMPK activity don't hold. Something that should actually be obvious, in view of the role AMPK plays skeletal muscle glucose uptake, glycogen and ATP regulation (Kurth-Kraczek. 1999; Musi. 2002), and mitochondrial biogenesis (Hardie. 2010).

Figure 3: Insulin, HOMA-IR, adiponectin and adiponectin relative to white adipose tissue weight in control, pair-fed (same food intake as ALA, but no supplement) and ALA supplemented rodents after 8 weeks (based on Prieto-Hontoria. 2013)

Still, due to the profound increases (total and relative to fat weight) in adiponectin (cf. figure 3), a fat-derived hormonal with well-established insulin-sensitizing and anti-obesity effects (Yamauchi. 2001; Shehzad. 2013), which showed a statistically significant correlation (after correction for adiposity) with the HOMA index, a recognized marker of insulin resistance, and its preventive effects against diet induced obesity, alpha lipoic acid should remain among the recommended supplements for obese, insulin resistant or diabetic subjects.

Is alpha lipoic acid for you? If you are lean, this study says "NO"!

Image 2: If you are the fat endo at the bottom, ALA could be for you. If you are the guy on the left, mild cutting and bulking w/out ALA is for your. And if you are on the right, you better spend your money on protein, creatine, BC/EAAs.

Its merit for lean physically active people, who consume a energetically appropriate whole-foods diet and strive to build a lean and muscular, not just a skinny physique, its usefulness is yet somewhat questionable. After all, the pair-fed animals had an equally low amount of body fat as their peers on ALA, but statistically significant more lean body mass; and I personally don't believe that it is a realistic assumption that these effects could be countered by simply eating more without having negative effects on the total amount of body fat you would accumulate on this heavy-duty bulk.

Your best bet would to try and "exercise away" the negative effects on  skeletal muscle AMPK expression, but let's be honest: Would you rather wear a helmet instead of simply stopping to hammer your head against the wall? You would, ha? In that case you are beyond help, I guess... go ahead then and do what works for your obese neighbor.

Note (I know someone is going to ask this): If anyone can show me peer-reviewed in-vivo data that confirms the constantly made claim that the physiological effects (not the petri-dish or XYZ-essay effects) of R-ALA are superior, not just on a gram-per-gram base, but qualitatively, tho those of the cheap and obviously less profitable racemic ALA (= natural mix of R- and S-ALA), I would be inclined to answer the question "wouldn't taking R-ALA maybe make a difference".

References:

• Hardie DG. Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc. 2011 Feb;70(1):92-9. Epub 2010 Nov 11.
• Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999 Aug;48(8):1667-71.
• Mulligan JD, Gonzalez AA, Stewart AM, Carey HV, Saupe KW. Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse. J Physiol. 2007 Apr 15;580(Pt. 2):677-84.
• Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002 Jul;51(7):2074-81. 
• 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. 2013 Jun 5. [Epub ahead of print]
• Segermann J, Hotze A, Ulrich H, Rao GS. Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels. Arzneimittelforschung. 1991 Dec;41(12):1294-8.
• Shehzad A, Iqbal W, Shehzad O, Lee YS. Adiponectin: regulation of its production and its role in human diseases. Hormones (Athens). 2013 Jan-Mar;11(1):8-20. 
• Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001 Aug;7(8):941-6.