Why R+ instead of racemic lipoic acid by DrMatt

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Glucorell-R:

Welcome to a whole new dimension in supplements.



Matt Rawluk, B.Sc. Biochemistry



Unless you’ve been hiding under a rock these last couple of years, you’ve probably heard something about R-Alpha Lipoic Acid (R-ALA for short). You’ve also probably heard some pretty outlandish tales which made you wonder whether or not the people making them had taken their medication lately. The fact is that Glucorell R from Anabolic Fitness is the BEST alpha-lipoic acid on the market – hands down. Here’s a little more to tell you why they’re the only company that will let you tap into the wealth of benefits offered by R-ALA, and what those benefits REALLY are.



“What is it?”

R-ALA is a naturally occurring substance which has seen extensive use in Europe due to its ability to rejuvenate and restore the liver, as well as its antioxidant properties. R-ALA is actually a fatty acid compound, but is unique in that it has a sulfur-sulfur bond at the distal end (away from the carboxylic acid end of the fatty acid). It is this sulfur-sulfur bond which provides the antioxidant properties of R-ALA, due to the fact that it is easily reduced. For example, R-ALA is a great scavenger of hydroxyl radicals; these radicals are easily able to attack at one of the sulfurs and attach to the molecule. After attachment, the –OH now on R-ALA is able to be disposed of safely by the body, either through fatty acid metabolism or through the passage of the –OH group to another antioxidant molecule such as Vitamin C (ascorbic acid) or Vitamin E (alpha-tocopherol).



“Radical, man!”
OK, so maybe my lingo is best saved for 1992, but the compounds I’m referring to didn’t go away with M.C. Hammer’s parachute pants and Madonna’s cone-shaped brassiere. Metabolism is sometimes a violent thing; many enzymes are forced to generate energetically unfavourable products such as free radicals (and other oxidants) in order to produce other substances necessary for life. These free radicals have been implicated in premature aging (sun damage is a result of UV-induced free radicals which cause thymidine dimerization in DNA), diseases of the liver (the liver is one of the hotbeds of radical production in the body, as it is forced to detoxify our bodies on a daily basis; long-term exposure has been implicated in diseases such as cirrhosis), and certain cancers (radicals + DNA = trouble waiting to happen)… It doesn’t take a genius to realize that minimizing free radicals in the body is key to good health and longevity. The free radicals produced in our bodies need to be neutralized as soon as possible to prevent them from reacting with something critical, with possibly disastrous consequences. This is where antioxidants come in. Antioxidants are much like an absorbent sponge which sucks up the radicals and puts them into a much less harmful form; the problem isn’t what happens to the antioxidants, it’s what happens when you don’t have enough antioxidants to go around.



“Lean on me…”
We’ve all heard this great song by Bill Withers… and strangely enough, it applies to R-ALA. The line “lean on me, when you’re not strong, and I’ll be your friend. I’ll help you carry on for it won’t be long, ‘til I’m gonna need somebody to lean on” is probably the best (and catchiest!) description of antioxidant regeneration in the body. The main players are Vitamins C and E, which we tend to consume as part of our daily diet, and Coenzyme Q, which we synthesize. The problem is, with today’s fast-food culture, many of us aren’t able to ingest enough of Vitamins C and E, or synthesize enough Coenzyme Q, to keep up with our own radical production. This is where R-ALA comes in. Antioxidants use each other to swap functional groups and regenerate each other (remember the –OH group from our hydroxyl radical?) – R-ALA is no different. By adding even a small amount of R-ALA to your daily diet, you can help your other antioxidants to do their job better because R-ALA will help to regenerate them – and R-ALA will act on its own to further reduce your free radical levels!



R-ALA also acts to increase glutathione levels in cells (glutathione is another sulfur-containing antioxidant), and is a cofactor in a number of enzymes which are involved in metabolism (one example of such enzymes is the group of alpha-keto acid dehydrogenases, critical in the citric acid cycle for the usage of metabolites such as alpha-ketoglutarate).



“I noticed that Glucorell-R includes additional Biotin…”
Yes, it does. This is because R-ALA can actually compete with Biotin in the body; without biotin supplementation, symptoms of biotin deficiency can actually manifest themselves. So, instead of making you go out and get biotin for yourself, we threw some in there for you! Now THAT’S service!


“OK, so R-ALA is just for old people, or people who are worried about radicals…”
WRONG! We’re just getting started. Let’s talk healthy, active people here – people like you and me. Most of us have a little bit of fat which we’d like to get rid of… come on, admit it – wouldn’t you like those love handles gone? Thighs tighter? Butt firmer? Somehow, no matter how much we’re able to lose with proper diet and exercise, these stubborn pockets of fat linger. Why? Because, for the most part, they’re insulin-resistant. Insulin resistance in fat pockets means that they are unresponsive to insulin signaling, and can occur for a variety of reasons (chronic hyperglycemia, genetic predisposition, receptor damage, etc.). The bottom line is that these fat pockets simply don’t respond the way the rest of the body responds to insulin. Because of this, the body secretes more insulin, which further downgrades the insulin response in resistant cells, which causes higher insulin secretion, which… well, you get the picture – and it’s not pretty. R-ALA has been shown to actually prevent or REVERSE insulin resistance in clinical studies. Remember the antioxidant properties we talked about earlier? Well, here’s an excerpt from a paper published by the University of Montreal:



“The antihypertensive action and the prevention of insulin resistance by lipoic acid appears to be associated with its antioxidant properties because it prevented the increase of oxidative stress…”

El Midaoui A and Champlain J (2002). Prevention of hypertension, insulin resistance and oxidative stress by alpha-lipoic acid. Hypertension 39(2):303-7.



By preventing or reversing insulin resistance, your body is able to PROPERLY respond to insulin. Proper response to insulin means your muscles are able to take up glucose from the bloodstream and utilize it for fuel – this reduces hyperglycemia and its associated negative effects. Not only is this good for your blood sugar, it’s also good for your body fat! Excess carbohydrate (like sugars) is the main reason that most of us accumulate fat. By allowing our muscles to remove sugars from the bloodstream effectively, thus lowering blood sugar levels, we simply don’t have the CHANCE to store the excess carbohydrate as fat! The significance of this fact will become clear in just a few seconds.



Also, notice they mentioned hypertension (high blood pressure) in the passage above. Not only does R-ALA help you burn excess fat by preventing/reversing insulin resistance, it lowers your blood pressure! I don’t know about you, but that’s definitely a side-effect I could get used to…



“Can you repeat that please?”
Let’s recap: R-ALA will decrease the level of harmful oxidants in your body, prevent or reverse insulin resistance, slow your conversion of carbohydrates into fats, normalize your blood sugar, and lower your blood pressure. Man, I’d hate it if all of that happened – wouldn’t you? But we’re not done yet!



“Gentlemen, start your engines…”
Okay, remember that bit about slowing your storage of ingested carbohydrates as fats? Well, if that’s a jab then this is the right roundhouse – R-ALA actually boosts your metabolic rate! No, I’m not kidding – R-ALA actually boosts your metabolic rate! The ‘engine’ of your body’s cells is their mitochondria. Mitochondria are organelles (organelles are to cells as your organs are to your body) which provide the cell’s energy via the metabolism of fuels like carbohydrates and fats (proteins are metabolized primarily in the cytosol of the cell, then the carbon skeletons of converted amino acids are used in the mitochondria). Bottom line: improve mitochondrial function, and you’ll increase your metabolic rate. Let’s take a look at what the labcoats over at University of California at Berkeley have to say about this one:



“… R-lipoic acid supplementation improves indices of metabolic activity as well as lowers oxidative stress and damage evident in aging.”

Hagen TM et al (1999). R-alpha lipoic acid supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J 13(2):411-8.



Look at the title of that paper - “… improved mitochondrial function … increased metabolic rate”; this is exactly what we’re talking about! Now here’s where it starts to get really interesting if you’re into burning fat. If R-ALA causes your consumed carbohydrates to be utilized by muscle tissue for fuel, it doesn’t leave much (if any) for your adipocytes (fat storage/metabolism cells which make up adipose tissue). Just as you get hungry, so do your adipocytes. And when your adipocytes go to raid the fridge for their midnight snack, and there’s no carbohydrate to be found, they decide on a nice big chunk of FAT. That’s right – the very cells which produced the fat in the first place are forced to break it down so that they can survive. And where do they break it down? You guessed it – the mitochondria! Less fat synthesis + increased fat breakdown = reduction or elimination of those stubborn fat pockets you’ve always wanted to get rid of.



“But how are the muscle and fat cells differentially affected?”

Many people ask how R-ALA can possibly make a difference when it up-regulates the expression of the insulin-sensitive glucotransporter GLUT4 in BOTH muscle and fat cells (myocytes and adipocytes). The answer is somewhat complicated… but then again, so is the body. While R-ALA does upregulate the expression levels of GLUT4 in both adipocytes and myocytes, we have FAR more skeletal muscle in your body than we have fat cells. Thus, while the clearance rate of blood glucose due to adipocytes does in fact increase briefly, the clearance rate due to myocytes increases dramatically simply because of the sheer amount of muscle which has increased its GLUT4 activity. In essence, the adipocytes are the runts of the litter who can’t quite elbow their way into the trough at feeding time… there’s simply too much muscle around. The bottom line: there just aren’t enough adipocytes to compete with the high demand placed on blood glucose by skeletal muscle.



“So how is GLUT4 activity controlled, from a mechanistic point of view?”

We get this question a lot as well… it makes me feel good to know that someone out there is just as much of a keener as I am when it comes to this sort of thing. At the same time, it makes me sad because I can imagine what their social life is like…



Let’s take a look at a paper from the Hospital for Sick Children in Toronto:



“…results indicate that R (+) alpha-lipoic acid directly activates lipid, tyrosine and serine/threonine kinases in target cells, which could lead to the stimulation of glucose uptake induced by this natural cofactor. These properties are unique among all agents currently used to lower glycaemia in animals and humans with diabetes.”

Yaworsky K et al (2000). Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia 43(3):294-303.



Now, you might have to take my word for it, but activation of specific kinases (and thus ATP dependence) is a hallmark of vesicular transport in cells. So, since we see activation of the kinase families listed above, we can postulate that GLUT4 is recycled using vesicles which bud off from the membrane and return to the cytoplasm when the insulin (or R-ALA) signal is removed. Upon the return of the signal, these vesicles localize and fuse with the membrane, placing the transporter once again in contact with the outside environment and thus allows it to take up glucose across the membrane and into the cell’s interior. Evidence that wortmannin, an inhibitor or PI-3-Kinase, abolishes R-ALA stimulated glucose uptake provides some evidence that the mode of action is vesicular formation/fusion since PI-3-Kinase is critical for vesicle-mediated processes.



How the R-ALA stimulates these various kinases would likely be through interaction with either a cell-surface receptor which causes a signaling kinase cascade, or directly with one of the numerous heterotrimeric G proteins which would lead to the same sort of event. It’s essentially a case of a possibly analogous pathway making sense in light of past evidence. Similar pathways exist for most, if not all, of the peptide hormones, neurotransmitters such as serotonin (5-HT) and epinephrine, and numerous other cell-signalling molecules – it just makes sense that a tried, tested, and true method would also be seen in the R-ALA mechanism since the final effects (multiple kinase activation) are so markedly similar. With the amount of research presently being done on R-ALA and its mode of action, a definite answer cannot be far behind.



“My training includes substances which cause liver damage…”

This is, admittedly, a bit of an aside – but many people have no idea how truly versatile – and valuable – R-ALA really is.



There’s no disputing the fact that users of 17-alpha alkylated substances (and users of other substances) can do serious damage to their livers if they use these substances too much or too long. Not to mince words, if you damage your liver past a certain point, you probably shouldn’t be making any plans for next year (or possibly even next week). Naturally, very few – if any – individuals reach this sort of crossroads, but I’m sure you see the point: protecting one’s liver is of paramount importance.



R-ALA is one of the most versatile and most useful compounds known to man when it comes to treatment or protection of your liver. But don’t take my word for it – talk to University of California at Berkeley:



“… alpha lipoic acid was also used as a therapeutic agent in a number of conditions relating to liver disease, including alcohol-induced damage, mushroom poisoning, metal intoxification, and CCl4 [carbon tetrachloride] poisoning. Alpha-lipoic acid supplementation was successful in the treatment for these conditions in many cases.”

Bustamante J et al (1998). Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med 24(6):1023-39.



Why take chances with 17-alpha alkylated substances when protection can be so close at hand? Now, we’re not saying that R-ALA is a miracle cure – if you’re going to abuse these substances, you’ll still suffer all of the ill effects (you can’t stop a tidal wave with a bucket, right?). However, it’s our belief that an investment in R-ALA is an investment in your future health.



“OK, that all sounds great… but what’s with the R?”

The R’s in R-ALA and Glucorell-R aren’t just for show – they’re a key piece of the puzzle when it comes to effectiveness of lipoic acid. To understand this a little better, let’s look at what this R business is all about.



“Mirror, mirror, on the wall…”

Some molecules which contain carbon have a distinctive property of being optically active. This means that they can rotate plane-polarized light in a given direction. The reason for this is because of a certain absolute configuration around one (or more) carbon atoms which are bound to 4 different groups. This property is called chirality, and a molecule which has one or more of these stereogenic centers (the name for carbons bound to 4 different substituents) is called a chiral molecule. For every stereogenic center, there are two relative configurations, called enantiomers. Enantiomers are distinguishable based on the fact that they are non-superimposable mirror images. Good examples of two enantiomers are your right and left hand. They’re mirror images of one another which can’t be superimposed. Make sense? Remember the hand analogy; it will become important later.



Now I know you’re probably wondering why you’re still reading, and I admit it’s not the most exciting thing you’ve probably ever read… but bear with me – this is all going somewhere. I’m just trying to help you better understand how some companies are ripping you off. Trust me, it will save you a lot of time, money, and frustration if you understand the difference between quality goods and half-baked ripoffs.



Let’s get back to the stereochemistry for a second here. Remember the enantiomer thing? Well, it’s no good to talk about enantiomers if we can’t name them. So, three scientists named Cahn, Ingold, and Prelog decided to devise a system of naming based on atomic-number-based prioritization (if you want more details, check out an organic chemistry textbook). These rules became known as the CIP (Cahn-Ingold-Prelog) rules and it’s these rules which give us the R (rectus; from the Latin meaning “right”) and S (sinister; from the Lating meaning “left”) designations. Incidentally, if you’ve ever seen L and D- designations, such as on a bottle of L-glutamine or L-carnitine, these are a different system of nomenclature quite often used for biological molecules which is based on the way that L-(-)- or D-(+)-glyceraldehyde (one of the first isolated optically active biological molecules) rotated plane-polarized light. D stands for dextrorotatory (rotating to the right) and L for levorotatory (rotating to the left). The D and L system cannot be related to the R and S system without actual experimental evidence, and is no longer used except for common, well-known molecules such as the L-amino acids and the D-sugars. A good example of a failure of the D/L system is D-(-)-lactic acid… but nevermind about that – we’re talking in terms of R and S as it pertains to lipoic acid.



Now, when most companies synthesize ALA, they do it in such a way that the result is what’s known as a racemate – an equal mixture of the R and S forms of ALA, which is costly and time-consuming to purify. But who cares – lipoic acid is lipoic acid, right? If you believe that, then I’ve got some great ocean-front property near Las Vegas that I’d love to sell you.



“When the left hand holds back the right…”

Here’s where all of your knowledge of stereochemistry pays off. Ready for it?



The R enantiomer of ALA is the ONLY enantiomer with significant, positive biological activity. It’s the ONLY enantiomer which does the things listed above – reduction of oxidative stress, reversal of insulin resistance, and boosting of metabolism – to any great degree. Need proof? Here are just two examples out of an entire LIST of papers:



“This study revealed a marked stereospecificity in the prevention of buthionine sulfoximine-induced cataract, and in the protection of lens antioxidants, in newborn rats by alpha-lipoate, R- and racemic alpha-lipoate decreased cataract formation from 100% (buthionine sulfoximine only) to 55% (buthionine sulfoximine + R-alpha-lipoic acid) and 40% (buthionine sulfoximine + rac-alpha-lipoic acid) (p<0.05 compared to buthionine sulfoximine only). S-alpha-lipoic acid had no effect on cataract formation induced by buthionine sulfoximine. The lens antioxidants glutathione, ascorbate, and vitamin E were depleted to 45, 62, and 23% of control levels, respectively, by buthionine sulfoximine treatment, but were maintained at 84-97% of control levels when R-alpha-lipoic acid or rac-alpha-lipoic acid were administered with buthionine sulfoximine; S-alpha-lipoic acid administration had no protective effect on lens antioxidants.”

Maitra I et al (1996). Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Biochem Biophys Res Commun 16;221(2):422-9.



“We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake], glycogen synthesis, and glucose oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-[-)-ALA had no significant effect.”

Streeper RS et al (1997). Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol 273(1 Pt 1):E185-91.



Not only this, but the S enantiomer can actually REDUCE the effectiveness of the R enantiomer – the opposite configuration can actually cause the opposite effect! Why? Because the S enantiomer has enough similarity to occupy the sites that the R enantiomer does, without being similar enough to cause biological activity. It’s like having a key that fits your keyhole, but it’s for someone else’s door – the key looks great, and it fits the lock, but in the end you’re still stuck outside in the rain because the door won’t open. Here’s another excerpt from the same paper:



“Although chronic R-(+)-ALA treatment significantly reduced plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. … Chronic R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer.”

Streeper RS et al (1997). Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol 273(1 Pt 1):E185-91.



In light of these studies, it should be painfully clear that supplement companies which sell you the racemate – and most of the others do – are RIPPING YOU OFF! Not only are they selling you sub-standard product, but it actually contains something which counteracts the good effects of its useful component! Talk about kicking the consumer while you’re down…



“So what’s so different about Glucorell-R?”

Glucorell-R is composed of PURE R-alpha lipoic acid. Let me say that again – each dosage of Glucorell-R contains 100mg of pure, active, R-ALA (plus the 500mcg biotin mentioned earlier). How do we do it? A proprietary process which yields the R form in high yields, without having to deal with the S form. This translates into better results for you, the customer, and better satisfaction for us – we can rest easy knowing that our products are the best they can possibly be.



“The bottom line…”

If you’re serious about burning fat, increasing your energy levels, protecting your liver, reducing oxidative stress, and increasing your overall health, invest in Glucorell-R today.



If you’re serious about burning money… well, I’m sure you know how to get in touch with the other guys.













About the Author:

Matt Rawluk holds a B.Sc. with Specialization in Biochemistry from the University of Alberta, one of the finest biochemical and medical research schools in North America. He has played over nine years of football, including several at the University level prior to medically-forced retirement, and has had experience with a wide variety of supplements and training methodologies. He is currently entering graduate studies (Ph.D.) in the Department of Biochemistry at the University of Alberta, and will be investigating the role that cyclin-dependent kinases play in the regulation of cell division with hopes that modulation of these enzymes might be used as a treatment for proliferative diseases such as cancer.




SELECTED REFERENCES:


R-ALA : GENERAL INFORMATION
1: Amer MA. Modulation of age-related biochemical changes and oxidative stress by vitamin C and glutathione supplementation in old rats. Ann Nutr Metab. 2002;46(5):165-8

2: Arivazhagan P, Ramanathan K, Panneerselvam C. Effect of DL-alpha-lipoic acid on mitochondrial enzymes in aged rats. Chem Biol Interact. 2001 Nov 28;138(2):189-98.

3: Arivazhagan P, Juliet P, Panneerselvam C. Effect of dl-alpha-lipoic acid on the status of lipid peroxidation and antioxidants in aged rats. Pharmacol Res. 2000 Mar;41(3):299-303.

4: Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH. Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med. 1998 Apr;24(6):1023-39. Review.

5: Cakatay U, Telci A, Kayali R, Sivas A, Akcay T. Effect of alpha-lipoic acid supplementation on oxidative protein damage in the streptozotocin-diabetic rat. Res Exp Med (Berl). 2000 Feb;199(4):243-51.


6: Coombes JS, Powers SK, Hamilton KL, Demirel HA, Shanely RA, Zergeroglu MA,
Sen CK, Packer L, Ji LL. Improved cardiac performance after ischemia in aged rats supplemented with vitamin E and alpha-lipoic acid. Am J Physiol Regul Integr Comp Physiol. 2000 Dec;279(6):R2149-55.

7: El Midaoui A, de Champlain J. Prevention of hypertension, insulin resistance, and oxidative stress by alpha-lipoic acid. Hypertension. 2002 Feb;39(2):303-7.

8: Hagen TM, Moreau R, Suh JH, Visioli F. Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid. Ann N Y Acad Sci. 2002 Apr;959:491-507. Review.

9: Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1870-5. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184.

10: Hagen TM, Vinarsky V, Wehr CM, Ames BN. (R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo Antioxid Redox Signal. 2000 Fall;2(3):473-83.

11: Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V,
Bartholomew JC, Ames AB. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999 Feb;13(2):411-8.

12: Hagen TM, Wehr CM, Ames BN. Mitochondrial decay in aging. Reversal through supplementation of acetyl-L-carnitine and N-tert-butyl-alpha-phenyl-nitrone. Ann N Y Acad Sci. 1998 Nov 20;854:214-23.

13: Hagen TM, Ingersoll RT, Wehr CM, Lykkesfeldt J, Vinarsky V, Bartholomew JC,
Song MH, Ames BN. Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9562-6.

14: Khanna S, Atalay M, Laaksonen DE, Gul M, Roy S, Sen CK. Alpha-lipoic acid supplementation: tissue glutathione homeostasis at rest and after exercise.
J Appl Physiol. 1999 Apr;86(4):1191-6.

15: Kocak G, Aktan F, Canbolat O, Ozogul C, Elbeg S, Yildizoglu-Ari N, Karasu
C; ADIC Study Group--Antioxidants in Diabetes-Induced Complications. Alpha-lipoic acid treatment ameliorates metabolic parameters, blood pressure, vascular reactivity and morphology of vessels already damaged by streptozotocin-diabetes. Diabetes Nutr Metab. 2000 Dec;13(6):308-18.

16: Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184-5.

17: Liu J, Killilea DW, Ames BN. Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L- carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1876-81. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184.

18: Lykkesfeldt J, Hagen TM, Vinarsky V, Ames BN. Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes--reversal with (R)-alpha-lipoic acid supplementation. FASEB J. 1998 Sep;12(12):1183-9.

19: Podda M, Tritschler HJ, Ulrich H, Packer L. Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency. Biochem Biophys Res Commun. 1994 Oct 14;204(1):98-104.


20: Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, Hagen TM. Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. FASEB J. 2001 Mar;15(3):700-6.

R-ALA : STEREOCHEMICAL SIGNIFICANCE
1: Adger B, Bes MT, Grogan G, McCague R, Pedragosa-Moreau S, Roberts SM, Villa R, Wan PW, Willetts AJ. The synthesis of (R)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step. Bioorg Med Chem. 1997 Feb;5(2):253-61.

2: Biewenga GP, Dorstijn MA, Verhagen JV, Haenen GR, Bast A. Reduction of lipoic acid by lipoamide dehydrogenase. Biochem Pharmacol. 1996 Feb 9;51(3):233-8.

3: Bunik V, Shoubnikova A, Loeffelhardt S, Bisswanger H, Borbe HO, Follmann H. Using lipoate enantiomers and thioredoxin to study the mechanism of the 2-oxoacid-dependent dihydrolipoate production by the 2-oxoacid dehydrogenase complexes. FEBS Lett. 1995 Sep 4;371(2):167-70.

4: Constantinescu A, Tritschler H, Packer L. alpha-Lipoic acid protects against hemolysis of human erythrocytes induced by peroxyl radicals. Biochem Mol Biol Int. 1994 Jul;33(4):669-79.

5: Freisleben HJ, Neeb A, Lehr F, Ackermann H. Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice. Arzneimittelforschung. 1997 Jun;47(6):776-80.

6: Haramaki N, Han D, Handelman GJ, Tritschler HJ, Packer L. Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid. Free Radic Biol Med. 1997;22(3):535-42.

7: Loeffelhardt S, Borbe HO, Locher M, Bisswanger H. In vivo incorporation of lipoic acid enantiomers and homologues in the pyruvate dehydrogenase complex from Escherichia coli. Biochim Biophys Acta. 1996 Sep 13;1297(1):90-8.

8: Loffelhardt S, Bonaventura C, Locher M, Borbe HO, Bisswanger H. Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex. Biochem Pharmacol. 1995 Aug 25;50(5):637-46.

9: Maitra I, Serbinova E, Tritschler HJ, Packer L. Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Biochem Biophys Res Commun. 1996 Apr 16;221(2):422-9.

10: Oehring R, Bisswanger H. Incorporation of the enantiomers of lipoic acid into the pyruvate dehydrogenase complex from Escherichia coli in vivo. Biol Chem Hoppe Seyler. 1992 Jun;373(6):333-5.

11: Patel MS, Hong YS. Lipoic acid as an antioxidant. The role of dihydrolipoamide dehydrogenase. Methods Mol Biol. 1998;108:337-46. No abstract available.

12: Pick U, Haramaki N, Constantinescu A, Handelman GJ, Tritschler HJ, Packer L. Glutathione reductase and lipoamide dehydrogenase have opposite stereospecificities for alpha-lipoic acid enantiomers. Biochem Biophys Res Commun. 1995 Jan 17;206(2):724-30.

13: Saengsirisuwan V, Kinnick TR, Schmit MB, Henriksen EJ. Interactions of exercise training and lipoic acid on skeletal muscle glucose transport in obese Zucker rats. J Appl Physiol. 2001 Jul;91(1):145-53.


14: Schempp H, Ulrich H, Elstner EF. Stereospecific reduction of R(+)-thioctic acid by porcine heart lipoamide dehydrogenase/diaphorase. Z Naturforsch [C]. 1994 Sep-Oct;49(9-10):691-2.

15: Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ. Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol. 1997 Jul;273(1 Pt 1):E185-91.

16: Sumathi R, Jayanthi S, Kalpanadevi V, Varalakshmi P. Effect of DL alpha-lipoic acid on tissue lipid peroxidation and antioxidant systems in normal and glycollate treated rats. Pharmacol Res. 1993 May-Jun;27(4):309-18.

17: Tang LH, Aizenman E. Allosteric modulation of the NMDA receptor by dihydrolipoic and lipoic acid in rat cortical neurons in vitro. Neuron. 1993 Nov;11(5):857-63.

18: Zimmer G, Beikler TK, Schneider M, Ibel J, Tritschler H, Ulrich H. Dose/response curves of lipoic acid R-and S-forms in the working rat heart during reoxygenation: superiority of the R-enantiomer in enhancement of aortic flow. J Mol Cell Cardiol. 1995 Sep;27(9):1895-903.

19: Zimmer G, Mainka L, Ulrich H. ATP synthesis and ATPase activities in heart mitoplasts under influence of R- and S-enantiomers of lipoic acid. Methods Enzymol. 1995;251:332-40. No abstract available.



R-ALA: ACTIVATION OF GLUT4 AND EFFECTS ON GLYCAEMIA

1: Estrada DE, Ewart HS, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H, Klip A. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes. 1996 Dec;45(12):1798-804.



2: Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, Henriksen EJ. The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Diabetes. 1996 Aug;45(8):1024-9.



3: Khamaisi M, Rudich A, Beeri I, Pessler D, Friger M, Gavrilov V, Tritschler H, Bashan N. Metabolic effects of gamma-linolenic acid-alpha-lipoic acid conjugate in streptozotocin diabetic rats. Antioxid Redox Signal. 1999 Winter;1(4):523-35.





4: Khamaisi M, Potashnik R, Tirosh A, Demshchak E, Rudich A, Tritschler H, Wessel K, Bashan N. Lipoic acid reduces glycemia and increases muscle GLUT4 content in streptozotocin-diabetic rats. Metabolism. 1997 Jul;46(7):763-8.





5: Konrad D, Somwar R, Sweeney G, Yaworsky K, Hayashi M, Ramlal T, Klip A. The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes. 2001 Jun;50(6):1464-71.





6: Maddux BA, See W, Lawrence JC Jr, Goldfine AL, Goldfine ID, Evans JL. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acid. Diabetes. 2001 Feb;50(2):404-10.





7: Yaworsky K, Somwar R, Ramlal T, Tritschler HJ, Klip A. Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia. 2000 Mar;43(3):294-303.

[LOOMZ]

Thanks for that one Ulter. That was a great read.

"I will act as if what I do makes a difference." William James

[SteveDFW]

Has anyone experienced any extra water retention around the waist when using R-ALA?

If so, was it dose dependent?

I have about 15 people to distribute this one to.
i've been preaching the benefits of R-ALA and
they think i'm just a supplement nut...

Thanks Ulter

Doggy

[ECM]

Could someone post a link to the original article? Or was this in a print magazine somewhere?

Thanks!

[mryanf]

I just noticed that some of the stickies have been disapearing this week and wanted to to throw out my vote for keeping this one up. This article should be mandatory reading for new members. I had forgoten about it until I read it again today. I am even going to show a copy to my wife to help justify my ever increasing expenditures.

Definitely keep up the good work. Thanks.

[Fonz]

This is what I´m in the proces of writing using applied math and bio-chemistry:

I will be expaining R-ALA´s effects on the muscles, fat cells, liver and other organs and how they relate to an igested oral glucose load composed of proteins/fats/carbs.
Basically, where the glucose flows to and from in the body after it has being ingested. This has never been fully explained bfore because quite simply the bio-chemical complexity and math required was unknown to me at the time. I will narrow it down once I have it finished though. After having done all that, I will explain how R-ALA affects all those interrelated bio-chemical systems in a positive way that ameliorates whole body composition.

I may ned help in some of the bio-chemistry though.

Fonz

"Great minds talk about ideas, average minds talk about facts, and weak minds talk about people"

---- Fonz 6/2002

[Fonz]

An excerpt:

EXCERPT OF PRIOR GLUCOMETRIC ANALYSIS

I’ll now take a small excerpt from my Glucometric Analysis; you can find it at CEM and at EF.

Meal = 500Kcal 6g Fat 14.3g Protein 98g Carbs

According to the equation represented above:

Total Glucose derived from ingested meal = 98g (carbs)+ 7.59g(protein) + 0.6g(fat) = 106.19g total glucose

Supplement #1: Placebo

Person was me. Weight: 82Kg(180.8lbs) Blood Volume(Explained below) = 6200ml

The total Area under the Blood Glucose Curve was 76.22 mg/dl (squared). A normal person of 70Kg has 5000ml of blood volume. The blood volume then increases in increments of 0.6L per 6Kg of body weight.

So, since I was the test subject, my standard weight was 82Kg(180.8lbs), and had therefore 6.2L or 6200ml of blood. So therefore, 76.22mg of glucose per decilitre in my blood(squared)

Initial BG Measurement: 48mg/dl Temp: 37.3C (99.1F)

(Eat Food as described above)

T+1hr Measurement: 90mg/dl Temp: 37.2C (99F)
T+2hrs Measurement: 40mg/dl Temp: 36.8C (98.2F)
T+3hrs measurement: 74mg/dl Temp: 37.1C (98.8F)
T+4hrs Measurement: 72mg/dl Temp: 37.2F (99F)

Area under positive BG Curve (Taking initial BG measurement as the horizontal) =

21 + 17.64 + 11.47 + 24 + 1 = 75.11 mg/dl (squared)

Area under initial BG measurement (negative):0.64 + 0.47 = 1. 11 mg/dl (squared)

Therefore the Total Area = 75.11 + 1.11 = 76.22 mg/dl (squared)


Here is where it gets interesting:
Blood Flow Analysis:

Since the blood vessel has a cross-sectional area, 1 decilitre = 0.1 Litres. This is the latter amount of fluid/blood which travels through the cross-sectional of the blood vessel.. Finding out the flow rate of the cross-sectional area of the given blood vessel flow can be done this way: Flow Rate = 1 decilitre = 0.1L = 100g Therefore, The Area = Pi * Radius(squared). Taking this into account, the Mass Flow-rate = 100g * Area. Which equals to: Mass Flow-rate = 100g * Pi * radius of cross-sectional blood vessel(squared). From reference books one can determine that the average sized blood vessel that carries blood, oxygen and nutrients etc… to parts of the human anatomy can be surmised to be approx: 3.5cm in diameter. Any larger and you run the risk of a rupture over the lifespan of the vessel. (This normally happens to people with Hypertension)

Now, one can say that the radius of the cross-sectional area in the blood vessel where the volume of blood flow saturated with the ingested glucose was flowing was approximately 3.5cm in diameter. Note: The measurement by the blood glucose machine is an area because the volumetric flow rate equation inside a fluidic cross-sectional area is due to the fact that the blood vessel is a circular area not a straight line. Therefore, the cross-sectional area of a blood vessel , Area of Blood vessel = Pi * Radius(squared) . So then, taking the diameter of an average sized blood vessel as described above, we get a radius of 1.75cm. Therefore, the cross-sectional area of the blood vessel now becomes: Cross-sectional Area of Blood vessel = Pi * ( 1.75cm)(1.75cm) = 9.6211 cm(squared).

And there´s more....and it pertains to explaining how R-ALA affects the glucose in the fat cells(triglycerides contain a glycerol component which makes fat 10% glucose), muscle and liver cells(Composed of glucose complexed with apprx. 4g water + potassium....whicg forms glycogen), and glucose being oxidized in the blood stream. I believe there´s a definate correlation between all of them, and the glucose in the fat, muscle, blood stream.Ultimately, with such a mathematical model one could explain how R-ALA´s glucose up-take increasing and oxidizing effects on all these bio-chemical components of human anatomy interact with each other.

This is juts an excerpt, the paper is much longer and a bit complicated...still trying to narrow down some of the mathematical jargon.

Fonz

"Great minds talk about ideas, average minds talk about facts, and weak minds talk about people"

---- Fonz 6/2002

[Fonz]

Finished Part I of the article...you have mail Ulter.

Fonz

"Great minds talk about ideas, average minds talk about facts, and weak minds talk about people"

---- Fonz 6/2002

[Fonz]

Lets see if Matt(as a Bio-chemist , having done applied math) finds this of interest:

Ingested Glucose Utilization Article (By Fonz) Part I (No R-ALA used) Part 2(W/R-ALA)

This is a bit complicated, but please bear with me.

Imagine you consume a macro-nutrient meal cmposed of carbohydrates, fats, and proteins. So, the original polynomial equation becomes, for the total ingested glucose load:

Glucose Ingested =

(Grams of Carbohydrates) * (1.0) + (Grams of Protein * (0.58) + (Grams of Fat * (0.1)

The equation can be explained in this fashion:

- Carbohydrates convert to glucose with 100%
efficiency
- Protein converts to glucose with approx. 58%
efficiency because there are glucogenic
and ketogenic amino-acids. (Keep in mind that
glutamine is glucogenic and comprises
close to 61% of the amino-acid pool in the
blood stream).
- Fat converts to glucose at a 10% conversion
rate due to the glycerol chain at the end
of the triglyceride(fat) molecule.

This equation just represents the total glucose load ingested by a person during a meal containing all macro-nutrients, Fats, proteins, and carbohydrates.

EXCERPT OF MY GLUCOMETRIC ANALYSIS

I’ll now take a small excerpt from my Glucometric Analysis, which you can find at CEM and at EF.

Standardized Meal(Bread) = 500Kcal 6g Fat 14.3g Protein 98g Carbs

According to the equation represented above:

Total Glucose derived from ingested meal =

(98g carbohydrates * 1.0) + ((14.3g protein * (0.58)) + (6g fat * (0.1)) = 98g + 8.29g + 0.6g = 106.89g total glucose ingested.

Supplement #1: Placebo

Person was me.

Weight: 82Kg(180.8lbs)
Blood Volume(Explained below) = 6200ml

(T=0hrs)
Initial BG Measurement: 48mg/dl Temp: 37.3C (99.1F)

(Eat Food as described above)

(T+1h) Measurement: 90mg/dl Temp: 37.2C
(99F)

(T+2hrs) Measurement: 40mg/dl Temp: 36.8C (98.2F)

(T+3hrs) measurement: 74mg/dl Temp: 37.1C (98.8F)

(T+4hrs) Measurement: 72mg/dl Temp: 37.2F
(99F)

Area under positive BG Curve (Taking initial BG measurement as the horizontal) =

21 + 17.64 + 11.47 + 24 + 1 = 75.11 mg/dl (squared)

Area under initial BG measurement (negative):0.64 + 0.47 = 1. 11 mg/dl (squared)

Therefore the Total Area = 75.11 + 1.11 = 76.22 mg/dl (squared)

The total Area under the Blood Glucose Curve was 76.22 mg/dl (squared) after the standardized meal. A normal person of 70Kg has 5000ml of blood volume. The blood volume then increases in increments of 0.6L per 6Kg of body weight. So, since I was the test subject, my standard weight was 82Kg(180.8lbs), and had therefore 6.2L or 6200ml of blood. So therefore, I had 76.22mg of glucose per dl(squared) in my blood in any given cross-sectional area of my blood vessels.


Here is where it gets interesting:

Blood Flow Analysis:

Since a blood vessel has a cross-sectional area, 1 decilitre = 0.1 Litres. This is the latter amount of fluid/blood which travels through the cross-sectional of the blood vessel.. Finding out the flow rate of the cross-sectional area of the given blood vessel flow can be done this way: Flow Rate = 1 decilitre = 0.1L = 100g(Assume that the density of blood is very close to 1g/ml) Therefore, The Area of the blood vessel = (Pi * Radius(squared)). Taking this into account, the Mass Flow-rate = 100g * Area of the blood vessel. Then, we can surmise that the Mass Flow-rate = 100g * Pi * radius of cross-sectional blood vessel(squared). From reference books one can determine that the average sized blood vessel that carries blood, oxygen and nutrients etc… to parts of the human anatomy in any normal healthy person can be surmised to be approx: 3.5cm in diameter.

Now, one can derive the radius of the cross-sectional area of the blood vessel where the volume of blood flow saturated with the ingested glucose is flowing. This number is approximately 1.75cm.. Note: The measurement by the blood glucose machine is an area because the volumetric flow rate equation inside a fluidic cross-sectional area is due to the fact that the blood vessel is a circular area(like a hose) not a straight line. If one where to use their imagination think of a line of bread crumbs(glucose in this case) going through a circular hose with a specific diameter. Now, the cross-sectional area of a blood vessel can be calculated as (A) = Pi * Radius(squared) . Since we can take the radius of an average sized blood vessel of a healthy male to be 1.75cm(See above). Then, the cross-sectional area of the blood vessel becomes: Cross-sectional Area of Blood vessel = Pi * ( 1.75cm)(1.75cm) = 9.6211 cm(squared).

Calculations:

So, the total area under the blood glucose curve as seen in the excerpt of my old glucometric analysis above is 76.22mg/dl(squared). But as a decilitre = 0.1L. 0.1L(squared) = 10000ml(squared). 10000ml(squared) being equal to 100 decilitres. From this, the new data becomes that glucose travels at 76.22mg per 10000ml of blood(which is equal to 100dl or 10L) after the ingestion of my aforementioned glucose load.. But, since my total blood volume was 6.2L(See the excerpt of my glucometric analysis) we can now surmise that the blood loaded with glucose goes through blood vessels with a cross-sectional area of approximately 9.6211cm(squared). Therefore, the total glucose travelling through the blood vessels of the body approximately after the initial glucose load is (76.22mg glucose per 10 Litres of blood). In 6.2L of blood(6200000mg), the amount of glucose present in the blood would be 76.22mg * (6.2L/10L)) = 47.2564mg of total glucose flowing around my entire blood plasma vessel structure. But now, we have to do the last part, and that is factor in the cross-sectional area of the blood vessels. From the blood flow analysis section: Mass flow-rate across a circular cross-section of a blood vessel = Mass(glucose(mg)) * Area(cm(squared)).

Therefore, Mass flow-rate = 47.2564mg (glucose) * 9.6211 cm(squared)

But now, we have to change dimensions. 0.0472564g = 47.2564mg
1 cm (squared) = 1.0 * 10exp(-4) metres squared. Then, 1cm(squared) = 1.0 * 10exp(-6) metres cubed. Therefore, 9.6211 cm(squared) = 9.6211 * 1.0 * 10exp(-4) metres squared = 0.0009621 metres squared. Therefore ultimately, 9.6211cm(squared) = 9.6211 * 1.0 * 10exp(-6) = 0.000009621 metres cubed.

Now using the dimensions we have derived:
(From my previous Glucometric Analysis)

Standardized Meal(Bread) = 500Kcal 6g Fat 14.3g Protein 98g Carbs

According to the equation I described above:

Total Glucose derived from ingested meal = 98g + 8.29g + 0.6g = 106.89g total glucose

Total glucose inside my blood supply after initial glucose load was: 47.2564mg of glucose. Total cross-sectional Area of an average blood vessel in cubic metres = 0.000009621. Now, one metre cubed = 1000Litres, therefore 0.000009621 metres cubed = 0.009621L. Which this can then be changed to decilitre format, or 0.09621dl.
So, therefore total linear area of blood is 0.09621dl And the glucose mass was 47.2564mg

Therefore, we are ready for the final phase.
Total Glucose content = 47.2564mg
Total Area Blood = 0.09621 decilitres.
But, we have to reduce the final equation to the standard mg/dl to compare glucose variances and losses.
Therefore, the final standard blood glucose measurement through a blood vessel becomes 47.2564mg/0.09621dl. Which if reduced proportionally in order for dl = 1(constant), you get: BG(measurement) for the entire body = (47.2564*10.3939)mg/dl = 491.178mg/dl

Now, the glucose load(initial) was 106.89g = 106890mg

Amount of blood plasma in my body = 6.2L = 62dl

Therefore, the BG measurement(whole body should read) = 1724.03mg/dl

Discussion:

There seems to be a discrepancy between the blood glucose level in the blood supply T=4hrs after ingestion ( 491.178mg/dl), and what was measured by the initial glucose load( 1724.03mg/dl). This seems to suggest that the orally ingested macro-nutrient meal described beforehand of a specific glucose load, was then diverted to the different organs of the body, - such as the muscle cells, fat cells, liver cells, oxidized for fuel, brain cells, etc… This I believe can be explained by the differential in the initial glucose load per unit blood after the ingestion of the original meal(in decilitres): 1724.03mg/dl, and then the subsequent drop in measured blood glucose levels afterwards(in decilitres): 491.178mg/dl.

These two numbers: Initial: 1724.03mg/dl and Final: 491.178mg/dl, indicate that
(100% - (491.178/1724.03) * 100%) = 71.51% of the original glucose load was used by the body for various uses. The rest was lost to unknown variances.

Converting it to grams, we get:

Initial load: 106.89g Glucose Final(measured) in blood vessels: 30.453g Glucose

The discrepancy being (106.89g – 30.453g) = 76.437g

Therefore, only 76.437g of glucose out of 106.89g of ingested glucose was used by the body under normal conditions.

Fonz

"Great minds talk about ideas, average minds talk about facts, and weak minds talk about people"

---- Fonz 6/2002

[archive_Evidence]

fonz, you're 100 pounds. SSSSHHHHHHHHHHHH!!!!!!
(that means be quiet nuclear wizard)