Alpha Lipoic Acid, GABA, Taurine, Green Tea, Gooseberry & Fenugreek. Plus: Metformin the No.1 Drug? Supplements to Improve and Restore Insulin Sensitivity - Serving #1

Don't forget, those caps and pills are not worth a penny without you committing to the all the lifestyle changes I outlined in episode one of this series.

I am well aware that you had to wait for a full week for this 2nd part of the "Restore & Maintain Insulin Sensitivity" Series (read part I), so I am going to make no words about it and get straight to the annotated list of useful supplements.

Just a reminder for the lazy asses: Don't even think about starting any of the supplements on the list, if you have not already cut your carbs to a low, but not very low level, got rid of all plain sugar in your diet, started to work out frequently, get enough sleep, avoid stims and control (not totally eradicate) your linoleic acid (omega-6) intake.

Here we go, for serving #1

In order to give you at least some guidance on where you may want to start, I will classify the supplements in 4 very broad categories with

• [A] for supplements that are almost certainly useful,
• [B] for supplements that are potentially useful and definitely worth trying,
• [C] for supplements that are marginally useful and probably worth trying, and
• [D] for supplements that are simply bullocks and not even worth trying

Whenever I feel confident to do so, I will also suggest a concrete dosage - in some cases, such as GABA, I can however neither do the former, nor the latter, because there simply is too little quality research out there.

• Did you know that continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction in women with PCOS who have long been advised to stop metformin during pregnancy (cf. Nawaz. 2008)?
  Metformin [A]: Technically it is not a supplement, but let's be honest, who except for the FDA cares? Many supplements work as effectively as pharmacological drugs, but as far as real insulin sensitizers are concerned metformin still appears to have the edge on the rest of the pack (supplement or drug): It has an excellent safety profile (even in gestational diabetes, which has long been thought of being the one area of application, where metformin was not the first line intervention of choice; cf. Lautatzis. 2013). It works via a similar mechanisms as dieting and exercise does (→ AMPK; this is actually imho it's main advantage - an advantage it shares with lipoic acid btw.). And metformin has only recently been shown not to inhibit the benefits of exercise on glycaemic control or fitness (Boulé. 2013).
  
  Moreover, hundreds of studies support the preventive effects of metformin against the manifestation of tumors of pancreas, breast, colorectum, liver, endometrium and ovary. The prognosis of diabetic cancer patients on metformin therapy seems be better, than in diabetics without metformin treatment (Anděl. 2013).
  
  So, if you belong those people who have real issues and not just slightly elevated blood glucose levels, have your metformin prescription filled - it's unquestionable an [A] among the agents that can help you restore your insulin sensitivity [I don't have to tell you that this is not an agent you would use simply to stay insulin sensitive, right?].
  
  One thing you should keep in mind though, is that it may lower your B12 levels. While this could be a simply results of increased usage and more recent studies question previous reports according to which metformin radically depletes B12 levels have been questioned lately, it probably won't hurt to take 500-1,000mcg of methylcobolamine alongside your metformin.
• Alpha lipoic acid (ALA) [A]: In a way lipoic acid, a naturally occuring organosulfur compound derived from octanoic acid, is a cousin of metformin. Unfortunately (for the future of alpha lipoic acid as an anti-diabetes agent and the diabetics who have ever since been treated with pro-obesogenic PPAR-agonists) the pharma industry realized that selling a natural and thus non-patentable anti-diabetes drug would not only generate a lower revenue, it would also hamper the sales of patentable and thus more profitable drugs.
  
  
  Don't take lipoic acid instead of working out. Why? Well, alpha lipoic acid has been shown to increase the arthesclerosis risk in a human trial by McNeilly et al. In the said study, 1g of alpha lipoic acid per day increased the cardiovascular disease risk, in 24 obese individuals with impaired glucose tolerance who participated in the experiment (McNeilly. 2012); the underlying mechanism was an increase in LDL oxidation that did albeit occur only in the "ALA only" but not the "ALA + exercise" group.
  Luckily, there are still more than enough animal and human studies (Jacob. 1999; Xiang. 2011; Porasuphatana. 2012) to support the beneficial effects lipoic acid will have on glucose management and hyperglycemic damage in (pre-)diabetics.
  
  In view of the fact that it could contribute to the development of heart disease precipitate hypoglycemic episodes (Khamaisi. 1990), has negative effects on appetite (which is the main mechanism by which it reduces weight gain in rodents) and appears to mess with lean mass gains - suggested reads ("You Could be Just as Lean, but More Muscular Without a Nutrient Repartitioner" (learn more); "Further Evidence Against Anti-Oxidant Supplementation: Vitamin E + Alpha Lipoic Acid Reduce Skeletal Muscle Mitochondrial Biogenesis" (read more) I would still not suggest you take high doses (>100-200mg) if you don't have problems with keeping your blood sugar levels in check.
  
  For those of you, who have established problems with managing their glucose levels, taking 2x250mg-600mg (with meals) would yet be a good point to start from (keep an eye on how it affects your glucose levels and adjust the dosage appropriately).
  
  With respect to the purported superiority of R-ALA vs. the regular (=racemic mixture) version of lipoic acid, I can only repeat that I am still waiting for someone to show me a study that would prove that R-ALA is more potent than regular the cheap racemic mixture that's been used in the vast majority of the currently available (mostly beneficial) studies.

• 

  Figure 1: GABA does effectively restore "almost" normal glucose levels in severly diabetic mice; the dosage is not mentioned in the FT or the supplemental material (Soltani. 2011)

  GABA [?]: No, the reason GABA (Gama-aminobutyric acid) is on the list is not that it will make you sleep better (although this may - for some(!) people, actually be the case). It's rather its direct protective and even restorative effect on pancreatic beta-cells (Soltani. 2011; Tian. 2013).
  
  Despite the fact that we have known about these effects for decades, up to now nobody seems to be interested to do or finance the research that would be necessary to make concrete and reliable dosage-recommendations. In fact, the evidence is still so scarce that we cannot even say: "Yes, GABA is definitely going to help" - if the prelminary evidence we have translates from the petri dish to the rodent cage and into the real world, it could however be the #1 agent on this list. Why? Well, this would basically mean that it could cure diabetes even when you have progressed from being insulin resistant to being a full-blown diabetic.

Beware of high dose GABA (>3g) supplementation on empty! Those 100mg of GABA are very unlikely to have any negative effects on your health. With higher amounts, on the other hand, specifically if they are taken on empty and thus rapidly absorbed, side effect can occur. Anxiety, slowed breathing, weakness, they all are probably caused by peripheral effects (not in the brain), but this does not make them desirable, either. So practically speaking this means that you best stick to low / divided doses and if you take more, take it with food.

• The best evidence we have that this could in fact be the case does probably come from a 2011 study by Soltani, who have actually taken the important step from the petri dish to the rodent model and were able to show that  GABA restores β-cell mass and reverses diabetes in severely diabetic mice.
  
  
  Warning: Don't start out with 5g of GABA in one serving - esp. not on an empty stomach. This is not only going to give you parestesia (tingles), but could also have you gasp for air and have problems keeping on your feet, due to the profound actions on peripheral GABA receptors.
  Furthermore, human studies from the eighties have shown that 5g and 10g of GABA (consumed orally) exert direct insulinotropic effects (remember insulin resistance is not about too much insulin, but about the latter having no / too little effect on glucose uptake) and since oral GABA does not cross the blood-brain-barrier it's safe to be consumed by humans in relatively high doses (cf. Cavagnini. 1982). Still, as in the case of lipoic acid, GABA is not patentable and the stocks of the big players in the anti-diabetes drug business would certainly take a tumble, when someone actually proved that you could reverse diabetes by simply taking X grams of GABA everyday.
• Taurine [B]: You will remember that I mentioned Taurine only 2 days ago in the context of the anti-diabetic effects of whey protein (read more). You will probably also remember the numerous previous posts on the beneficial effects of taurine specifically for people with diabetes or pre-diabetes (learn more about taurine). I will therefore stick to a brief overview of the direct and indirect (protection against negative effects of high blood glucose) benefits taurine has to offer for people with insulin resistance and high glucose levels.

  • 

    Figure 2: The effects of taurine supplementation on glucose and insulin (top, left & right) 0, 6, and 12 weeks after beginning the taurine-supplemention in OLEFT rats (rodent model of diet induced diabesity), as well as the reaction to an insulin tolerance test and corresponding changes in insulin sensitivity (bottom, left & right; adapted from Kim. 2012).

    Taurine shows "independent of hypoglycemic effect in several animal model" (Ito. 2012)
  • It ameliorates both high glucose and lipid levels (Kim. 2012)
  • Taurine improves NO mediated blood glow in the corpus cavernosum (=battles erectile dysfunction) due to diabetes (Dalaklioglu. 2013)
  • Taurine exerts cardio-protective effects, partly via direct effects on the angiotensin II type2 receptor expression (Li. 2005)
  • It restores normal platelet aggregation in diabetics (Franconi. 1995)
  • Taurine protects the kidneys (Yao. 2009)
  • Taurine reduces mortality risk upon long-term administratio (rodent model; Franconi. 2004) 
  • It has a higher ability to reduce insulin resistance and stronger antioxidant properties than the diabetes drug glibenclamide (El Zahraa. 2012)
  • It protects the eye from diabetes induced damage (Hansen. 2001 Kim. 2007)
  • Taurine has protective effects against all components of the metablic syndrom (Hansen. 2001; Imae. 2012)
  • It increase the levels of conjugated tRNA, restore respiratory chain activity, and increase the synthesis of ATP at the expense of superoxide anion production (Schaffer. 2009)
  Beta alanine is the taurine antagonist #1: SuppVersity readers should know that (read more), but I guess I better repeat it: The "best" way to deplete taurine levels is the ingestion of copious amounts of beta alanine 24/7 (the side effects are similar to those of diabetes related taurine depletion, eg. Waterfield. 1993 → lowered protection against CCL induced liver damage). From a performance perspective there is as of now no evidence that you would need more than 2.5g of beta alanine per day, anyway. So why would you want to waste money and cellular taurine on additional beta alanine ;-)
  It should be mentioned thought that there are also studies which did not support the beneficial results reported above - they are not numerous, but may yield some insights into effective vs. uneffective dosage regimen.
  
  The 1.5g/day the overweight subjects with a predisposition for developing diabetes the subjects in a 2004 study by Brøns et al. received, may for example simply have been too little to exert any effects (Brøns. 2004). Based on the human equivalents of rodent studies, it appears most promising to distribute a daily taurine intake of 3g to max. 6g over your three main meals.
  
  Since taurine does also act as a gaba-ergic small molecule neurotransmitter (Albrecht. 2005), I would yet suggest you keep a close eye on (a) initial sedative effects and (b) longer term increases in anxiety - both of which have been reported in animal studies with allegedly higher and / or intracerebral administration of taurine.
  
  The effects on neurotransmitters, the diarrhea some users experience (esp. when they take it without food) and the fact that many, but by far not all studies confirmed direct inusulin sensitizing effects of taurine are the reason I'd still classify it as [B] level supplement - certainly one of the better ones, but still only "possibly beneficial".

• 

  Table 1: Within group changes in randomized controlled GTE supplementation study involving 20-65 year old type 2 diabetics with BMI > 25 kg/m² (Hsu. 2012)

  Green tea extract [C]: GTE can help with insulin sensitivity in two different ways. Firstly, it will help control the inflammatory processes that are (partly) responsible for the development of insulin resistance and it will secondly help you to "cut carbs" by simply blocking their digestion and assimilation (Forester. 2012; Williamson. 2013).
  
  And while the real world benefits of GTE supplementation in a 2012 study by Hsu et al. were not statistically significant, it may still be worth trialling a dose of 3x 200-500mg per day. That being said, unless you are specifically looking for the stimulant effects of GTE, you should consider using a decaffeinated extract because you do not really need the additional caffeine (cf. part I of this series). 
  
  The reason I still classified GTE as [C] as in "marginally useful" is that the study by Hsu is not the only human trial that did not find significant effects on insulin sensitivity. It is rather one of the few where you could actually argue that - though not significant - it may have had an independent effect on glucose management. In the majority of studies "green tea exhibited limited benefits in reducing FBS or HbA1c levels" and as Ruitang Deng puts it in his recent review: "Should not be recommended for managing hyperglycemia." (Deng. 2012) This does not mean that it cannot help ameliorate the side effects, but we are looking for agents that will actually help you lower your blood glucose levels and in this regard green tea extracts are only marginally useful.

• 

  Amla, gooseberry, or Emblica Officinalis call it whatever you want, but don't expect too much - it may work, but it's no comparison to the [A]-class supplements. Moreover, the results from the available human study could be distorted by additional ingredients in the supplement formulas the scientists used.

  Gooseberry (emblica officinalis) [C]: Studies by Mitra (2007), Faizal (2009), Iyer (2009) and Chen (2011) all provide evidence that the ingestion of extracts from Indian gooseberry (=Amla), an edible fruit from trees of the phyllanthaceae family can effectively improve blood glucose management.
  
  Due to the fact that the Gooseberry extract was administered in conjunction with other agents, it is however difficult to suggest an effective dosage, but it appears as if 100-150mg per day of gooseberry extract would be enough.
  
  In Iyer et al. even a single serving of fresh amla (~35g) got the job done, but the overall effect size is rather mediocre, thus Gooseberry is only "possibly useful" [C]. 
• Fenugreek [B]: Also known as trigonella foenum-graecum L., fenugreek belongs to the plant family fabaceae (or leguminosae).
  
  

  

  Figure 3: Relative changes in response to glucose challenge (glucose AUC, glucose half-life and metabolic clearance rate) in 5 non-insulin dependent diabetic patients after consuming a diet supplemented with 25 g fenugreek seeds daily for 15 days; the data is expressed relative to the values the scientists measured in five likewise diabetic control subjects (Raghuram. 1994)

  Fenugreek seeds and extracts from the leaves have a decent amount of studies to support its anti-hyperglycemic effects - including clinical studies with human volunteers showing that dosage of only 500 mg of seed or leaf extracts given once or twice daily either alone or in combination with standard, synthetic anti-diabetic drugs such as metformin and glipizide provided beneficial effects on controlling plasma glucose levels (Deng. 2012).
  
  The reason I'd still classify it as [B] are (a) the fact that it takes a huge amount of the seeds (e.g. 25g; see figure 3) to elicit significant effects and (b) the fact that studies using extracts yielded ambiguous results. Contrary to the whole seeds, of which it seems that they exert their beneficial effects by similar mechanisms as dietary fiber, leaf extracs appear to exert a direct insulin sensitizing effect.
  
  In a study by Abdel-Barry et al. from the year 2000, 40 mg/kg aqueous extract powder from fenugreek leaves(!) in 10 mL distilled water lowered the glucose levels of 20 healthy male volunteers aged 20-30 years by 13.4% 4h after ingestion. Unfortunately, the hunger, frequent urination and dizziness one third of the subjects complained about, was not the only side effect - the subjects also had significantly reduces serum potassium levels; an observation of which the researchers rightly state that it warrants further investigation to ensure the long-term safety of fenugreek leaf extracts.
  
  Bottom line? Well, once again "possibly useful", but only if you actually have problems with insulin resistance and high blood sugar.

"What? Where is there rest?" In case this is pretty much what you are thinking right now, I can calm you down, there will be at least another serving of pro-insulin sensitivity supplements. I simply don't have the time to write more today, but did not want to go back on my promise from last Sunday. So, be patient, there is going to be more: Promising supps such as cinnamon, vinegar, or grape seed extract, for example but also questionable stuff such as bitter melon or legume extracts.

References: 

• Abdel-Barry JA, Abdel-Hassan IA, Jawad AM, al-Hakiem MH. Hypoglycaemic effect of aqueous extract of the leaves of Trigonella foenum-graecum in healthy volunteers. East Mediterr Health J. 2000 Jan;6(1):83-8.
• Anděl M, Skrha P, Trnka J. [Metformin: the overlap of diabetology and oncology]. Vnitr Lek. 2013 Aug;59(8):738-42. 
• Boulé NG, Kenny GP, Larose J, Khandwala F, Kuzik N, Sigal RJ. Does metformin modify the effect on glycaemic control of aerobic exercise, resistance exercise or both? Diabetologia. 2013 Aug 23. 
• Brøns C, Spohr C, Storgaard H, Dyerberg J, Vaag A. Effect of taurine treatment on insulin secretion and action, and on serum lipid levels in overweight men with a genetic predisposition for type II diabetes mellitus. Eur J Clin Nutr. 2004 Sep;58(9):1239-47.
• Cavagnini F, et al. Effects of gamma aminobutyric acid (GABA) and muscimol on endocrine pancreatic function in man.Metabolism. 1982; 31:73–77. 
• Chen TS, Liou SY, Wu HC, Tsai FJ, Tsai CH, Huang CY, et al. Efficacy of epigallocatechin-3-gallate and amla (Emblica officinalis) extract for the treatment of diabetic-uremic patients. J Medicinal Food. 2011;14:718–23.
• Dalaklioglu S, Kuscu N, Celik-Ozenci C, Bayram Z, Nacitarhan C, Ozdem SS. Chronic treatment with taurine ameliorates diabetes-induced dysfunction of nitric oxide-mediated neurogenic and endothelium-dependent corpus cavernosum relaxation in rats. Fundam Clin Pharmacol. 2013 Jun 14. 
• Deng R. A review of the hypoglycemic effects of five commonly used herbal food supplements. Recent Pat Food Nutr Agric. 2012 Apr 1;4(1):50-60.
• El Zahraa Z El Ashry F, Mahmoud MF, El Maraghy NN, Ahmed AF. Effect of Cordyceps sinensis and taurine either alone or in combination on streptozotocin induced diabetes. Food Chem Toxicol. 2012 Mar;50(3-4):1159-65. 
• Faizal P, Suresh S, Satheesh Kumar R, Augusti KT. A study on the hypoglycemic and hypolipidemic effects of an ayurvedic drug Ra-janyamalakadi in diabetic patients. Indian J Clinical Biochem. 2009;24:82–7.
• Mitra A. Effects of a composite of tulsi leaves, amla bitter gourd, gurmur leaves, jamun fruit and seed in type 2 diabetic patients. J Clinical Diagnostic Research. 2007;6:511–20.
• Forester SC, Gu Y, Lambert JD. Inhibition of starch digestion by the green tea polyphenol, (-)-epigallocatechin-3-gallate. Mol Nutr Food Res. 2012 Nov;56(11):1647-54.
• Franconi F, Bennardini F, Mattana A, Miceli M, Ciuti M, Mian M, Gironi A, Anichini R, Seghieri G. Plasma and platelet taurine are reduced in subjects with insulin-dependent diabetes mellitus: effects of taurine supplementation. Am J Clin Nutr. 1995 May;61(5):1115-9.
• Franconi F, Di Leo MA, Bennardini F, Ghirlanda G. Is taurine beneficial in reducing risk factors for diabetes mellitus? Neurochem Res. 2004 Jan;29(1):143-50.
• Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med. 1999 Aug;27(3-4):309-14.
• Hansen SH. The role of taurine in diabetes and the development of diabetic complications. Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):330-46. 
• Hsu CH, Liao YL, Lin SC, Tsai TH, Huang CJ, Chou P. Does supplementation with green tea extract improve insulin resistance in obese type 2 diabetics? A randomized, double-blind, and placebo-controlled clinical trial. Altern Med Rev. 2011 Jun;16(2):157-63.
• Imae M, Asano T, Murakami S. Potential role of taurine in the prevention of diabetes and metabolic syndrome. Amino Acids. 2012 Dec 8.
• Ito T, Schaffer SW, Azuma J. The potential usefulness of taurine on diabetes mellitus and its complications. Amino Acids. 2012 May;42(5):1529-39. doi: 10.1007/s00726-011-0883-5. Epub 2011 Mar 25.
• Iyer U, Joshi A, Dhruv S. Impact of Amla (Embilica Officinalis) supplementation on the glycemic and lipidemic status of type 2 diabetic subjects. J Herbal Medicine and Toxicol. 2009;3:15–21.
• Khamaisi M, Rudich A, Potashnik R, Tritschler HJ, Gutman A, Bashan N. Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats. Metabolism. 1999 Apr;48(4):504-10.
• Kim SJ, Ramesh C, Gupta H, Lee W. Taurine-diabetes interaction: from involvement to protection. J Biol Regul Homeost Agents. 2007;21(3-4):63-77.
• Kim KS, Oh da H, Kim JY, Lee BG, You JS, Chang KJ, Chung HJ, Yoo MC, Yang HI, Kang JH, Hwang YC, Ahn KJ, Chung HY, Jeong IK. Taurine ameliorates hyperglycemia and dyslipidemia by reducing insulin resistance and leptin level in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term diabetes. Exp Mol Med. 2012 Nov 30;44(11):665-73.
• Lautatzis ME, Goulis DG, Vrontakis M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: A systematic review. Metabolism. 2013 Jul 22. 
• Li C, Cao L, Zeng Q, Liu X, Zhang Y, Dai T, Hu D, Huang K, Wang Y, Wang X, Li D, Chen Z, Zhang J, Li Y, Sharma R. Taurine may prevent diabetic rats from developing cardiomyopathy also by downregulating angiotensin II type2 receptor expression. Cardiovasc Drugs Ther. 2005 Mar;19(2):105-12.
• Mitra A. Effects of a composite of tulsi leaves, amla bitter gourd, gurmur leaves, jamun fruit and seed in type 2 diabetic patients. J Clinical Diagnostic Research. 2007;6:511–20.
• McNeilly AM, Davison GW, Murphy MH, Nadeem N, Trinick T, Duly E, Novials A, McEneny J. Effect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance. Lipids Health Dis. 2011 Nov 22;10:217.
• Nawaz FH, Khalid R, Naru T, Rizvi J. Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome? J Obstet Gynaecol Res. 2008 Oct;34(5):832-7. 
• Porasuphatana S, Suddee S, Nartnampong A, Konsil J, Harnwong B, Santaweesuk A. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study. Asia Pac J Clin Nutr. 2012;21(1):12-21. 
• Raghuram TC, Sharma RD, Sivakumar B, Sahay BK. Effect of fenugreek seeds on intravenous glucose disposition in non-insulin dependent diabetic patients. Phytotherapy Research. 1994;8:83–6.
• Schaffer SW, Azuma J, Mozaffari M. Role of antioxidant activity of taurine in diabetes. Can J Physiol Pharmacol. 2009 Feb;87(2):91-9.
• Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, Chakrabarti R, Ng T, Jin T, Zhang H, Lu WY, Feng ZP, Prud'homme GJ, Wang Q. GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11692-7.
• Tian J, Dang H, Chen Z, Guan A, Jin Y, Atkinson MA, Kaufman DL. GABA regulates both the survival and replication of human ss-cells. Diabetes. 2013 Aug 30. 
• Williamson G. Possible effects of dietary polyphenols on sugar absorption and digestion. Mol Nutr Food Res. 2013 Jan;57(1):48-57.
• Xiang G, Pu J, Yue L, Hou J, Sun H. α-lipoic acid can improve endothelial dysfunction in subjects with impaired fasting glucose. Metabolism. 2011 Apr;60(4):480-5.
• Yao HT, Lin P, Chang YW,Chen CT, Chiang MT, Chang L, Kuo YC, Tsai HT, Yeh TK. Effect of taurine supplementation on cytochrome P450 2E1 and oxidative stress in the liver and kidneys of rats with streptozotocin-induced diabetes. Food Chem Toxicol. 2009 Jul;47(7):1703-9

The Intracrine Effects of Anabolic Steroids - Metanolone Promotes Stretch-Induced Intramuscular MGF Expression

Arnold's workout regimen are known to generate a hell lot of wear and tear and actually this could be part of his success formula.

I have to admit that the increase in intra-cellular MGF production is probably not the only, but certainly a new and very important pathway by which anabolic steroids "actively" promote muscle growth. According to a recent study from the Department of Rehabilitation and Physical Medicine, Graduate School of Medical and Dental Sciences at the Kagoshima University in Japan (Ikeda. 2013) anabolic agents such as metenolone which is a naturally occuring, WADA-listed long-acting anabolic steroid with weak androgenic (testosterone or androsterone-like) properties. It is isolated from the glands of pregnant domesticated felines, and is supplied as the acetate ester for oral administration and as the enanthate ester for intramuscular injection. Adult doses for the treatment of aplastic anemia are usually in a range of 1–3 mg/kg per day (Wikipedia).

Stretch-induced muscle growth

For the rodents in the study at hand the scientists did escalate the dosage and pumped roughly 10mg/kg (this is already the human equivalent) into the critters.

Then, the right gastrocnemius muscles were stretched repeatedly by manual ankle dorsiflexion 15 times per minute for 15 min. The contralateral muscles were not stretched as a control. In the control rats (n=6), the gastrocnemius was stretched as for the treatment group, but no metenolone was injected. Twenty-four hours after the procedure, the rats were sacrificed by injection of a lethal dose of sodium pentobarbital and their medial gastrocnemius muscles removed on both sides.

Actually, I suspect the sacrifice would not have been necessary as the extraction of the MGF, or as the scientists call it the "the specific autocrine IGF-I splicing variant mechano-growth factor" is something you can measure from a muscle biopsy. So, the only argument against a human study, is probably the dosage and the general administration of anabolic steroids to human subjects.

Figure 1: Treatment effects on MGF, MyoD, Myogenin (a.u.) in rats w/w/out metenolone injection (Ikeda. 2013)

With the highly significant effects on MGF and the non-significant effects on myoD and myogenin, both of which are involved in the recruitement of new muscle nuclei from the stem cell (satellite cell) pool in the musculature, the result of the study is yet of generic nature and will almost certainly apply to humans as well.

Sketch of a mammalian skeletal muscle fiber - myonucleus (turqouis), mitochondria (blue),  sarcoplasmic rectilium (buff), tubules (orange), myofibrils (pinkish)

Artist: Lesley Skeates. Originally from Gray's Anatomy 29th ed. Elsevier. 2008

Stretch to grow? It's not the act of stretching, but rather the wear and tear to the cells that is interpreted as being worked out heavily that induces muscle growth and most importantly structural adaptation (in other words a "stretch during a lift will do just as well as deliberate stretching). The downstream effects of these intracrine (=confined within the cell itself) reactions go way beyond simply pumping more protein into the existing muscular structure.  In a previous study, Ikeda et al. have already shown that "[e]ither continuous or repetitive short duration stretching of muscles for 1 week increased the mRNA expression levels of MyoD, myogenin, and embryonic MyHC relative to those of unstretched  muscles." (Ikeda. 2003)

The latter are markers for the often hailed activation, recruitment and replenishment of muscle "stem-", or "satellite cells", of which you know from the Muscle Hypertrophy 101 (read it) that they are what allows you to grow beyond the natural limit, a limit that makes the muscle of myostatin negative animals huge, but dysfunctional - a direct result of the structural changes not being able to keep pace with the constant influx of protein (learn more).

And with the effects of MGF being related to the important strength facilitating effects of exercise and the underlying cause of the changes being a simple stretch of the musculature the results put another emphasis on the necessity of the "wear and tear" for your body to make the necessary adaptations to exercise

---

Figure 2: Illustration of what you should have learned, if you read all installments of the Intermittent Thoughts on Building Muscle (read summary)

So what exactly is he result of the study then? I guess the elevator pitch is: Study confirms the facilitative role in skeletal muscle restructuring / growth of anabolic steroids. If you want more details, I suggest you go back to the "Intermittent Thoughts on Building Muscle Series" and educate yourself about IGF-1, MGF, GH, testosterone, myostatin and co and their specific roles in skeletal muscle hypetrophy (see "reading assignment).

Figure 2, to the right delivers a sneak peak of what you can expect and if that's not attractive enough, I'd suggest you use the "Preliminary Conclusion - Exercise, mTOR/AKT/MAPK, IGF-1, Testosterone, Estrogen, DHT, Nutrition, Supps & Sleep" (read it) of the series as a cognitive anabolic to promote your interest ;-)

I already hinted at that in a previous paragraph, but I think it's still worth repeating in the bottom line that despite being derived in a rodent study with an "exotic" anabolic agent, there is no question that the results of the study at hand will also be relevant for chemical athletes and little evidence they would not apply to

Your reading assignment for today:

1. IGF-1 and its Splice Variants MGF, IGF-IEa & Co - Are the growths hormones master regulators of muscle growth or just a bunch of cogs in the wheel of skeletal muscle hypertrophy?
   
   
2. IGF-1, TNF-α, IL-15 & Co and the Emerging Role of an Auto-/Endocrine-Immune Axis in Skeletal Muscle Hypertrophy  - How does inflammation factor in, is it beneficial or detrimental?
    
3. Zoning in on "The Big T" - Does testosterone (alone) build muscle?
    
4. Quantifying "The Big T" - Do increases of testosterone, which are well within the physiological range matter?
    
5. Understanding the "Big T" - How does testosterone work? What is its effect on stem cells and how come it makes you leaner?
    
6. Estrogen, Friend or Foe of Skeletal Muscle Hypertrophy? - Which role does estrogen play and why could you SERM away your growth potential, when you (ab-)use tamoxifen or potent aromatase inhibitors?
    
7. Dihydrotestosterone (DHT), The All Things Male Hormone - Will it make you bigger, stronger and faster or just balder, fatter and unhealthier?

References:

• Ikeda S, Yoshida A, Matayoshi S, Tanaka N. Repetitive stretch induces c-fos and myogenin mRNA within several hours in skeletal muscle removed from rats. Arch Phys Med Rehabil. 2003 Mar;84(3):419-23.
• Ikeda S et al. The Effect of Anabolic Steroid Administration on Passive Stretching-Induced Expression of Mechano-Growth Factor in Skeletal Muscle. The Scientific World Journal. 2013: Article ID 313605.

Confirmed: All Wheys, Not Just Hydro Whey Boost Glucose Uptake And Liver + Muscle Glycogen Supercompensation. Plus: How Could Taurine Be Involved in This Benefits?

Do it or don't? If the question is about consuming whey protein, the answer is clear: Do it! Use whey!

As a diligent student of the SuppVersity you will remember my previous article "The Glucose Repartioning Effects of Isoleucine: Falsely Underappreciated BCAA and Its Dipeptides Maximize GLUT-4 Expression and Ramp Up Muscular Glucose Uptake" (read more). If you don't let me briefly bring you up to speed in back in February, I told you about the beneficial effects of a class of isoleucine peptides in whey protein hydrosylate [as the study at hand goes to show you, this is important, see bottom line] on glucose transporter (GLUT-4) expression and thus glucose uptake in skeletal muscle.

Today I am pleased to be able to continue and expand on this discussion based on the results of the latest study from the same group of researchers from Sao Paulo, Brazil (Morato. 2013).

Whey, an anti-diabetic glycogen supercompensation tool

As Morato et al. point out, their own study is by no means the only one that supports the very special insulin sensitizing activity of whey proteins. In fact, whey is already touted as potential anti-diabetic. If the medical orthodoxy or rather it's "legislative" arm was not trapped by its own dogmas WPH [whey protein hydrolysate] would already be a central part of the dietary recommendation for type II diabetics. With the current study being the first to show that a whey protein based diet will lead to chronically increased GLUT-4 expression and thus help to lower blood glucose and improve glycogen storage, the study at hand is albeit similarly interesting for the average musclehead and his obese type II diabetic neighbor.

Figure 1: Effects of casein, whey and whey hydro(lysate) diets on GLUT-4 expression, baseline insulin, liver glycogen and muscle glycogen levels (g/100g tissue; Moreto. 2013)

Apropos obese neighbor. You should go and convince him to go to the gym with you. After all, the rodent data in figure 1 clearly shows that WPH leads its trumps only when it is combined with training - in this case treadmill running for 60 minutes at 15 m/min (the exercise took place 16 h before the sacrifice; so the increases are not in response to the exercise! they are just amplified by chronic endurance during).

Suggested read: "The Overlooked Glucose Repartioning Effects of Isoleucine" (read more)

While exercise alone is well known to boost GLUT-4 expression and subsequent glucose uptake significantly (Christ-Roberts. 2004; Kuo. 2004; note. GLUT-4 activity correlates with the degree of muscular clycogen depletion, so no "5 min rest, 2 sets all out and go home workouts!"), the addition of a whey protein hydrosylate with a pre-hydrolysation level of 12.5% (think of it as being enzymatically "pre-digested) as the sole protein component of the baseline diet (15% protein total, 7% fat from vegetable oil, 68% carbs from sugar and corn starches) of the 48 male Wistar rats in the experiment at hand did turn the +100% increase from exercise alone into a  +160% increase.

I have to admit, the increased GLUT-4 uptake per se may not be news, but this is in fact the first chronic feeding study where it was observed in conjunction with higher glycogen levels - ca. 90%, 70% and a whopping 400% in the heart, the musclulature and the liver in the sedentary state for both WPH and regular whey protein. That's certainly impressive, but you got to remember that this is a result of combining whey with a high carbohydrate diet (69% of the diet vs. 7% fat) which provides the necessary readily available substrate for optimal glycogen super-saturation (=packing in more glycogen than you usually could).

You will and can very well live with the insulin spike!

Though it may not look like it in figure 1, you got to be aware that the values were not taken right after the ingestion of a meal, let alone a protein shake. In other words, it is almost certain that the whey protein groups will have had higher insulin levels immediately after a meal (note: Casein is still way more insulinogenic than meat or eggs).

I've gone into quite some detail on why insulin spikes (in the presence of glucose) are not a problem, but rather a vital necessity in a previous post (read it)

"One of the primary means to increase the concentration of GLUT-4 in the plasma membrane is through insulin-regulated trafficking (Zorzano. 2005). However, in the present experiment, no increase was noted in serum insulin levels in the groups consuming WPH.

The experimental design of the study focused on the moment of greatest mobilization of glucose transporter-4, and the animals were sacrificed 2 h after consuming the meal; this was too long an interval to observe the maximum plasma insulin response." (Morato. 2013)

It is thus a given that the  GLUT-4 translocation was at least supported by profound and temporary (at least in the presence of an adequate carbohydrate intake, their temporary nature is what makes the whey induced insulin spikes physiologic and beneficial vs. pathological and detrimental as chronic elevations would be; learn more). According to Morato et al. this is however not the only way the ingestion of whey affected the translocation of GLUT-4 (upstream) and the subsequent uptake of glucose into the muscle and liver (downstream):

Translocation of GLUT-4 to the PM [plasma membrane] can also be stimulated in an insulinindependent manner. Carneiro et al. (2009) accomplished this through taurine activation of the insulin pathway, thus raising the GLUT-4 concentration in the plasma membrane independent of insulin. However, the molecular mechanism behind this effect has still not been elucidated (Carneiro. 2009).

There is actually evidence that would suggest that whey protein hydrolysate is not simply not superior, but actually inferior to regular whey proteins when it comes to improvements in body composition in athletes (read more)

In the exercised animals of the WP and WPH groups, the plasma concentrations of taurine (Table 1) were greater (p,0.05) than those in the control group consuming CAS. This could explain, at least in part, the greater translocation of GLUT-4 in the WP and WPH groups.

After investigating the amino acid composition of the WP and WPH, it was found they were rich in sulfur amino acids (Table 2), and methionine and cysteine are endogenous precursors of taurine. Thus, the consumption of WP or WPH provided a greater amount of substrate for the endogenous production of taurine than casein, and the presence of this amino acid may have facilitated activation of the insulin pathway and cell capture of glucose, as indicated in the literature." (Morato. 2013; my emphases)

That's quite a surprising insight, isn't it? I mean, as a SuppVersity reader you have long known about the anti-diabetic prowess of taurine, but who would have suspected that it could be #3 alongside the active isoleucine dipeptides and the insulin release among the mechanisms behind the profound beneficial effects whey has on glucose? I mean, there is basically no taurine in whey.

SuppVersity readers have known for years, that whey is far superior to an amino acid (AA) mixture with the same AA make-up (read more)

Bottom line: Yep, this is support for a previous advice I've gicen: You better never run out of whey protein for both, health and performance reasons. Personally, I am yet most fascinated by the potential involvement of endogenous (=your body's own) taurine synthesis. That 's certainly going to be a topic in Sunday's 2nd installment on supplements to improve and maintain insulin sensitivity (read part I on lifestlye modifications here).

Pratically speaking the most important and eventually less surprising message of the study at hand is however that it does not necessarily have to be whey protein hydrolysate. The regular whey protein did an outstanding job, as well, and the "real-world" = visible / noticeable differences are propably non-significant.

In this context, some of you may also remember the results from another recently published study by Lollo et al. (read it) which did in fact suggest that the muscle building and body recompositioning effects of whey hydrolysate are inferior and not superior to those of regular whey.

References:

• Carneiro EM, Latorraca MQ, Araujo E, Beltra M, Oliveras MJ, et al. Taurine supplementation modulates glucose homeostasis and islet function. J Nutr Biochem. 2009; 20: 503–511.
• Christ-Roberts CY, Mandarino LJ. Glycogen synthase: key effect of exercise on insulin action. Exerc Sport Sci Rev. 2004; 32: 90–94.
• Kuo CH, Hwang H, Lee MC, Castle AL, Ivy JL. Role of insulin on exercise-induced GLUT-4 protein expression and glycogen supercompensation in rat skeletal muscle. J Appl Physiol.  2004; 96: 621–627.
• Morato PN, Lollo PC, Moura CS, Batista TM, Carneiro EM, Amaya-Farfan J. A dipeptide and an amino acid present in whey protein hydrolysate increase translocation of GLUT-4 to the plasma membrane in Wistar rats. Food Chem. 2013 Aug 15;139(1-4):853-9.
• Zorzano A, Palacín M,Gumá A. Mechanisms regulating GLUT 4 glucose transporter expression and glucose transport in skeletal muscle. Acta Physiol Scand. 2006. 183: 43–58.

Meta-Analysis Says: Fish Oil Does Not Help You Lean Out! Plus: Why It's Still Worth Having Fatty Fish 1-2x/Week

SuppVersity readers know: Diet (and exercise) will make you lose weight. Supplements can only accelerate the process. However, it it really possible that fish oil does not even do that?

I guess those of you who are still taking it, will already have noticed that there is nothing to the whole hoopla about the "fat burning effects of DHA & EPA". A recent meta-analysis from the University of Sheffield in the United Kingdom does now confirm just that: The hypothesis that daily fish oil supplementation reduces body weight and BMI is not supported by scientific evidence -at least not in the overweight and obese study participants of the 9 studies that met the rigorous criteria of this meta-analysis.

The scientists had conducted a search of Web of Science, PubMed, Medline and Google Scholar for studies having the keywords ‘fish’, ‘fish oil’, ‘oily fish’, ‘omega three’, ‘omega-3’, ‘n-3’, ‘body weight’, ‘body composition’, ‘BMI’, ‘weight reduction’ or ‘weight loss’ in them.

SuppVersity Sneak Peak: While it may not be directly related to fish oil, it will certainly border on the issue of weight and more importantly fat loss, as well: Today's Special of the SuppVersity Science Round-Up (tune in live at 12PM EST) discussing all you need to know about endogenous and exogenous (=supplemental) DHEA (not to be confused with DHA ;-) No idea what that could be? Well, what about adrenal fatigue, insulin resistance, low / high testosterone, aromatization, dosages, clinical & anecdotal evidence, etc. EDIT: Due to technical difficulties the show is going to be postponed. I will let you know on Facebook, when I know the day it will be aired (probably sometime next week, not necessarily Thursday).

From the query results, they filtered all papers that were not based on randomized controlled trials, had not compared the effect of fish oil supplementation with another (non-n-3) oil control [this is actually pretty interesting, because many trials simply throw the omega-3s on top of the regular diet and who can say that a spoon of olive oil would not have had similar, if not even more pronounced effects], had not used overweight or obese subjects and had not taken pre- and post-intervention measurements of body weight and BMI. Actually the fact that all of what they were left with were only 9 study is at least in my humble opinion an important result of this meta-analysis that tells you something about the "quality" of the omega-3 supplementation research out there.

Figure 1: Whether the participants received fish (FO) or placebo oil (PO) supplements did not make a difference; in fact, the results look (but aren't) slightly better in the placebo trial, usually (Harden. 2013)

The data I compiled in figure 1 gives you an overview of the results of the meta-analysis. It's not difficult to see that the remaining 9 studies clearly indicate that it is unrealistic to expect any direct effect on diet and/or diet + exercise induced weight loss.

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Bottom line: While the weight loss effects of fish oils are in fact totally overblown, it should not be overlooked that their beneficial effects on the inflammatory processes that are particularly pronounced during phases of weight gain can ameliorate (but not blunt) many of the ill health effects that arise as a consequence of the steady increase of the adipose organ. I have previously discussed the possibility of becoming what scientists love to celebrate as "healthy obese" person by soothing the sickening inflammation that would otherwise increase with every pound of extra-weight. Now you would thus still end up being fat, but you would get rid of the fat much easier and most importantly without permanent damage to your health.

Figure 2: Effects of 2.8 g/day omega-3 supplement on reductions in weight, waist and hip width in severely obese women on very low carb, very  low fat low protein 550kcal diets (Kunesova. 2005)

Based on studies by Kunesova and Hlavaty from the years 2005 and 2008, respectively, n-3 supplementation can also offset the negative effects of crazy low carb + low energy diets, as they are used to treat severely obese men and women, they can keep the fatty acid composition of the serum lipids normal and help enhance body weight and more importantly body fat on low carb diets (as signified by the superior reduction in waist circumference; cf. figure 2) loss.

So, irrespective of whether you are trying to lose or gain weight, the 1-2x servings of fatty fish I would recommend as a preferred source of omega-3 fatty acids should remain a staple of your diet. If not for weight loss purposes, then for their beneficial effects on your overall health.

Additional reads:

• "Phospholipid or Triglyceride? What's in Your Fish Oil Caps? Only Phospholipid Based DHA+EPA Reduces Fat Cell Growth & Elevated Insulin Levels Despite Obesogenic Diet" | read more
• "The Pro-Diabetic Effects of Shark Liver Oil - Plus: Can it Be Coincidence that the Omega-6-Laden Nigella Sativa Oil has Just the Opposite Effects on Blood Glucose & Triglycerides" | learn more
• "Obese Vegan Salmon!? Vegetable Oils and Proteins Reduce DHA and EPA Content by -28% and Increase Overall Adiposity and Triglyceride Levels in Atlantic Salmon." | get the details
• "Fish Oil W/ High Peroxide Levels Is Useless and Can Negate the Beneficial Health Effects of an Omega-3 Rich Diet. Plus: 3 Tips to Help You Make the Right Fish Oil Choices" | learn more
• "Making the Right Fish Choices: Fatty Acid Contents of 33 Different Fish Species. Plus: What Are the Implications?" | make the right choice

References:

• Harden CJ, et al. Preliminary meta-analysis of the effect of fish oil on body weight and body mass index in overweight and obese subjects does not support a link. Proceedings of the Nutrition Society(2013), 72 (OCE4), E283
• Hlavatý P, Kunesová M, Gojová M, Tvrzická E, Vecka M, Roubal P, Hill M, Hlavatá K, Kalousková P, Hainer V, Zák A, Drbohlav J. Change in fatty acid composition of serum lipids in obese females after short-term weight-reducing regimen with the addition of n-3 long chain polyunsaturated fatty acids in comparison to controls. Physiol Res. 2008;57 Suppl 1:S57-65.
• Kunesová M, Braunerová R, Hlavatý P, Tvrzická E, Stanková B, Skrha J, Hilgertová J, Hill M, Kopecký J, Wagenknecht M, Hainer V, Matoulek M, Parízková J, Zák A, Svacina S. The influence of n-3 polyunsaturated fatty acids and very low calorie diet during a short-term weight reducing regimen on weight loss and serum fatty acid composition in severely obese women. Physiol Res. 2006;55(1):63-72. Epub 2005 Apr 26.

Tabata Workouts: Do They Work & How Energy-Demanding Are They? 14.5 Kcal/Min Sounds Nice, But You Must Earn It!

Tabata training is intense: So if you don't have the guts to do it on your own, find someone to suffer next to you. Trust me that'll keep you going, if you'd have long surrendered if you had trained alone. Some gyms even offer special courses.

Most of you will probably be familiar with the ultra-short + ultra-intense HIIT prescription that's known as the Tabata protocol. Not really? Well, here is the elevator pitch, then:  "Tabata training," was first described by the Japanese scientist Izumi Tabata in 1996. Tabata and his colleagues (Tabata.1996) conducted a study that compared moderate-intensity continuous training at 70% of maximal oxygen consumption (VO2max) for 60 minutes, with HIIT conducted at 170% of VO2max. The HIIT training consisted of eight, 20-second all-out exercise bouts followed by 10 seconds of rest for a total of 4 minutes of exercise. Based on what you have read about the contemporary HIIT research here at the SuppVersity, you will be aware that Tabata's protocol is more intense, but also much shorter than the currently favored HIIT regimen with their ~1-4min (sometime even 8min!) intervals at 80-100% intensity.

Now, the "original" study found that HIIT improved aerobic capacity to a similar degree as moderate intensity continuous training (aka LISS). Nevertheless, it did resulted in an impressive +28% increase in anaerobic capacity.

Tabata 2.0? Is it time for a modification?

Meanwhile Tabata training has evolved to include a variety of modes and exercises. What has always remained an essential characteristic of this type of HIIT training, though are the classic 20-10 patterns (i.e., 20 seconds of all-out effort followed by 10 seconds of rest).

According to Talisa Emberts, John Porcari , Scott Doberstein, Jeff Steffen and Carl Foster, the general physiological effects of this type of training are well documented. What would be lacking, however, is data on the the relative exercise intensity and energy expenditure of Tabata training (Emberts. 2013). Therefore, the purpose of the study at hand, which comes right from the labs of the Department of Exercise and Sport Science at the University of Wisconsin, was to determine the u exercise intensity and energy expenditure of a Tabata workout.

What did the scientists do?

In order to measure the energy expenditure, the researchers recruited 16 trained volunteers (8♂: 35.3 ± 8.1 years, 1.81 ± 0.06 m, 93.7 ± 8.70 kg, 53.2 ± 0.6 ml·kg·min -1; 8♀: 28.4 ± 9.3 years, 1.71 0.09 m, 71.9 ± 12.0 kg, 42.9 ± 11.3 ml·kg·min -1). After the usual initial fitness tests, each subject completed two identical workouts.

Table 1: .Exercises included in the 20-minute Tabata workout; each exercise was repeated twice at a ratio of 20 sec exercise/10 sec rest

• workouts consisted of four, 4-minute "segments".
• segments consisted of performing the exercises listed in table 1 twice in succession.  

• subjects completed as many repetitions of each exercise as possible in 20 seconds followed by 10 seconds of rest.

• there was 1 minute of rest between each segment.  

As Emberts et al. point out, they "chose to do the four segments of Tabata in succession, since one of the criticisms of Tabata training has been that individuals cannot burn a sufficient number of calories in 4 minutes to favourably impact energy balance" (Emberts. 2013)

Figure 1: Energy expenditure per minute and total energy expenditure in 20 vs. 4 min TABATA studies (Emberts. 2013; Olsen. 2013)

A brief glimpse at the data in figure 1 goes to show you that the relative energy expenditure per minute was as impressive as in previous studies:

"Caloric expenditure averaged 14.5 ± 2.7 kcal·min -1 , which is very similar to the value found by Olsen (2013), who reported a slightly lower value of 13.4 kcal·min -1 . This was probably due to the fact that her study included 13 women and only 3 men. Total energy expenditure ranged from 240 to 360 kcals for the 20-minute workout, which is significantly higher than the estimated 54 kcals expended during the 4 minutes of exercise reported by Olson." (Emberts. 2013)

What was also impressive, though, was the rate of perceived exertion (RPE), which averaged 15.4  ±  1.3 for the two workouts and was that rated as "hard" by these already trained subjects. I mean, ask yourself what an untrained individual would have been telling you after high knee runs, plank punches, jumping jacks, side skaters, rope jumping, in/out boats, line jumps, push-ups, burpees, russian twists, squats, lunges, mt. climbers, push-ups, split squats and box jumps... right probably nothing: The average sedentary inhabitant of the Western Obesity Belt would simply have collapsed after two exercises ;-)

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If you are a pro (and I mean "are" and not think of yourself as one) looking for an intense workout that will help you cut body fat and gain muscle at the same time, look no further. The cross-fit protocol Smith et al. used in a study I wrote about earlier this year has what you are looking for - unfortunately it has a similarly insane intensity: "From 16% to 8% Body Fat in 10 Weeks: Crossfit Workout Gets The Leanest Shredded - But Only the Fittest Survive" (learn more).

240-360kcal/s in 20 min - is that worth it? It stands out of question that trained individuals who are willing and able to give their muscles and more importantly their central nervous system the recovery time they will need after these workouts will greatly benefit from the intensity of a Tabata routine like this. This is after all, the "uncomfort zone" in which someone with years of training experience under his / her belt can still enforce adaptation.

Contrary to the trained athlete, for whom the total amount of energy expenditure is secondary to proving new "growth" (the word refers to general growth as in increases not just in muscle power or size, but also overall conditioning) stimuli, the rookie and even many intermediate trainees are however going to be overwhelmed by the physical (some also by the mental) demands of this workout. For him / or her, a combination of strength training and LISS (rookie, or someone trying to cut weight) or strength training and "regular" HIIT (advanced trainee) may be thus in fact be  better choice. Not necessarily because it would burn more calories, but rather in view of the fact that it is not as overtraining prone as a 20min session of Tabata training.

References:

• Olson M. Tabata  interval  exercise:   Energy  expenditure and post-exercise responses. Medicine & Science in Sports & Exercise 45. 2013; S420.
• Emberts T, Porcari J, Doberstein S, Steffen J, Foster C. Exercise Intensity and Energy Expenditure of a Tabata Workout. Journal of Sports Science and Medicine. 2013; 12:612-613

Glutamine, a Better Glucose Source Than Glucose? Can You (Ab-)Use It As an Intra-/Post Workout Supplement? Human Study Suggest: Yes You Can! 8g Will Do the Trick

Could it be better to use glutamine as the main energy source in an intra-workout beverage? Or is the latter superior to glucose, only when it's already to late, meaning only, when you already are hypoglycemic?

I see the irritation on your face. How on earth should glutamine be a better glucose source than glucose: Adel obviously has lost his mind under the pressure of putting out interesting stuff on a daily basis... well, while the latter may be true (how would a sane person do what I do?), I am actually just reformulating the main message of a recently conducted study from the State University of Maringá in Brazil. In the corresponding paper, which was published online in the International Journal of Endocrinology (Nunes Santiago. 2013).

So yes, glutamine is in fact the better glucose...or maybe I should clarify it is a superior source of glucose to promote glycemia recovery after insulin-induced hypoglycemia. In other words, it will help you to lose the dizziness, the tiredness, the shaking and the sweating that are only a handful of the symptoms of low blood sugar (=hypoglycemia) more readily than glucose.

How do the scientists know?

Actually Nunes Santiogo et al. tested not just glucose and glutamine, they also provided their rodents which had been injected with a non-lethal but profoundly hypoglycemic dose of 1U/kg insulin at the beginning of their experiment with either of these substances:

alanine
glutamine, or
saline (control group)
• glucose
• glycerol
• lactate

The dosage was identical (100mg/kg) for all of them, so that we had a "level playing field". Now, if I had not given away all the information right in the headline, you would probably have expected glucose to rule, right?

Figure 1: Glucose (mg/dl) levels after administration of 100mg/kg of saline, glucose (Glu), glycerol (Gly), lactat (Lac), Glutamine (Gln) or alanine (Ala) to hypoglycemic mice (Nunes Santiago. 2013)

What? Your money was on Lactate? Well that's actually a smart choice, as well and shows me that you have been attentive over the past months.

A note on lactate: In view of the results of a recent study that showed that lactate may not be able to completely replace glucose, but can modulate metabolic and neuronal activity in a way that the glucose contribution to brain metabolism under hypoglycemic conditions is restored to levels otherwise only observed at euglycemia (Herzog. 2013), it is likely that it could sooth the symptoms of hypoglycemia without even replenishing blood glucose to normal. Well, as long as it is buffered (NaHCO3 ;-) and is not converted to lactic acid, at least.

Yeah, lactate is an emergency fuel, so it does not seem totally unlikely that it works, but if you take a look at the study outcome in figure 1 you will realize that glutamine was not just a notch, but rather significantly more effective in getting the ~70% reduced glucose levels back up in the normal zone. It's also better than the #1 source of gluconeogenesis alanine, which in turn was still superior to "the real deal", i.e. glucose.

The glucose, diabetics, for example are so desperate to find ("Where's my Snickers?"), when they realize that they are about to go hypo after an insulin injection or workout, on the other hand, brought the levels back up to only 63% and was thus only slightly better than lactate of which I already hinted at in the box to the right that the actual blood sugar levels may not adequately reflect the symptoms, due to it's ability to modulate the energy flux to the brain.

How could that be? Why is glutamine more effective than glucose?

It still sounds odd, I know, so let's see what the scientists have to say about their own results:

"In contrast with rats, oral glutamine showed better glycemia recovery compared with alanine (Figure 1). This difference could be attributed to the possibility that in mice the catabolism of glutamine in the enterocytes is lower than in rats" (Nunes Santiago. 2013)

Now this is a problem, because it makes the usual question of whether or not these results apply to human beings, or not even more difficult to answer. Are we more like rats or rather like mice? And what would be the perfect "blood sugar restoration agent" for us - Glucose or glutamine. I honestly cannot answer this question, but I can still give you a decent bottom line, I guess.

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Suggested read: "Post-Workout Glycogen Repletion - The Role of Protein, Leucine, Phenylalanine and Insulin. Plus: Protein & Carbs How Much do You Actually Need After a Workout?" | read more

Bottom line: Irrespective of whether it is "optimal" it is certainly a viable way to keep your glucose up and even replenish your glycogen levels after a workout by supplementing with l-glutamine. In 2005, for example, Iwashita et al. were able to show that 8g of glutamine promote storage of muscle glycogen to an extent similar to 330ml of 8.5% (wt/vol) glucose polymer solution (Bowtell. 1999); and this would not work if the glutamine was not turned into glucose by the liver and transported to the muscle in the blood stream so that it will - at least for as long as it disappeared in the skeletal muscle glycogen stores - also be available for the brain, the heart and all the other organs.


Whether things look different in insulin induced hyperglycemia is questionable, but I tend to think that 99% of you are interested in it's use as a workout / post-workout fuel in exchange for carbs and not so much as a means to save your life, when you you've been overdoing your slin shots.

If that's what you want to do, the optimal strategy would be to combine both. According to Bowtell et al. this will increase the non-oxidative glucose disposal by another +25%. This would also have the advantage that you are not overtaxing the glyconeogenic pathway in the liver. A potential overload of the latter is by the way also the reason why I strongly advise against trying to live off glutamine let alone other not as readily metabolized amino acids as your sole source of glucose (or energy in general).

Additional reads:

• "30g of oral glutamine have similar effects on GLP-1 as 75g of glucose" | read more
• "7 Rarely Thought of Side Effects of High Dose Glutamine" | read more
• "Chronic High Dose BCAA Supplementation Reduces Endurance Performance by 43% Plus: How Ammonia, Glutamine, Arginine & Low Carb Could be Involved" | read more
• "New Role for Glutamine in Protein Synthesis? Study Suggests Direct Effects on Mammalian Target of Rapamycin (mTOR) - EAAs Alone Won't Produce Optimal Results" | read more
• "Use Glutamine to Heal the Gut and Hinder Your Gut Bacteria from Eating Away Your BCAA, Arginine and Other Aminos" | read more

References: 

• Bowtell JL, Gelly K, Jackman ML, Patel A, Simeoni M, Rennie MJ. Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise. J Appl Physiol. 1999 Jun;86(6):1770-7.
• Herzog RI, Jiang L, Herman P, Zhao C, Sanganahalli BG, Mason GF, Hyder F, Rothman DL, Sherwin RS, Behar KL. Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. J Clin Invest. 2013 May 1;123(5):1988-98. 
• Nunes Santiago A, Ferreira de Godoi-Gazola VA, Milani MF, et al. Oral Glutamine Is Superior Than Oral Glucose to Promote Glycemia Recovery in Mice Submitted to Insulin-Induced Hypoglycemia. International Journal of Endocrinology, vol. 2013, Article ID 841514, 7 pages, 2013.

Medium Intensity Interval Training (MIIT) Increases Fitness of Overweight Sedentary Women Slower, But Eventually Just As Effectively as HIIT. Neither Cuts Fat / Body Weight

It does not always have to be "all out", but 70% is probably the minimum for intervals - esp. for the non-obese.

If you know all SuppVersity articles by heart, the name Astorino may ring a bell. I mentioned a previous study by Todd A. Astorino in my 2012 article "Are You Still Burning Calories or Already Losing Fat? Study Shows: 5x15 Min HIIT Reduce Body Fat & Improve Fitness Twice as Effectively as 5x40min of Classic Cardio" (read more). In their most recent study, the researchers from the Department of Kinesiology at the California State University took another look at HIIT exercise for the average female US citizen, to be precise. And the observation they made is actually quite astonishing.

MIIT vs. HIIT: Can both be equally effective?

In this group of healthy sedentary (<1h/week of regular physical activity) women (n=30; age 18-40; BMI >35kg/m²) it did effectively not make a difference, whether the participants trained at a high or medium intensities.

As you can see in figure 1, over time, both workouts yielded the exact same increases in VO2Max (marker of cardiovascular fitness)., What is however significantly different is the slope and the general look of the VO2max graph.

Figure 1: Study design and results of the 12-week intervention; training was performed 3 days/week on a cycle
ergometer and consisted of 6–10 bouts of 1 min duration at the given intensities; the asterisk after the week # indicates that the intensity values were adapted to the increase in W-Max over the past weeks (Astorino. 2013)

While the latter is clearly logarithmic for the high intensity interval training arm (HIIT; intensities see figure 1, left), the MIIT (LO in figure 1) VO2Max development is much more linear and does not display the same ceiling effect you see in the HI group. It would thus be reasonable to argue that...

MIIT hits HIIT, but...

... it is VERY likely that this is a "overweight woman phenomenon". After all, the heart rate was essentially the same regardless of whether the ladies worked out at an average intensity of 176W (MIIT) or 202W.

Figure 2: Heart rate and workload develoment over the 12-week study period (Astorino. 2013)

At first that may seem odd, but to push your heart rate through the 200 mark, you actually need a pretty decent fitness level. If you have been sitting around your whole life, you will be up to 190bpm when you simply take the stairs instead of the elevator; and while this is no health benefit it makes the same walk in the park that's just a nasty way of locomotion for the average athletic person an intense workout for the morbidly obese.

And what do we know about "intense workout"? Right, those are the true "cardio workouts" adaptation does not happen in the comfort zone and it does not entail weight loss (!) - I don't know how often I have to repeat that, but weight loss happens in the kitchen. You can only steer and promote what and how much you lose by working out... but that's the topic of another article.

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"Men are different women, too..." We all know that, but can we still train together or will women have to do cardio first, while men would be better off starting out lifting weights? (learn more)

Bottom line: If you, family or friends are starting out to work out - keep things at a pace that's intense for YOU - not for whomever you are trying to emulate or you are training with. If there is one beauty of doing cardio in the gym instead of outside, it is that you can train right next to a friend at your personal intensity level.

So don't put a spoke into your own wheels by trying not too look bad in front of a friend. Stick to your own tempo and use yourself as a reference to judge your progress - and if the latter looks like the orange graph in figure 2 (right) you know you are on track, no matter what the absolute wattage (or RPMs) say.

References:

• Astorino TA, Schubert MM, Palumbo E, Stirling D, McMillan DW, Cooper C, Godinez J, Martinez D, Gallant R. Magnitude and time course of changes in maximal oxygen uptake in response to distinct regimens of chronic interval training in sedentary women. Eur J Appl Physiol. 2013 Sep;113(9):2361-9.

Restore & Maintain Insulin Sensitivity - Basics: Turn Your Lifestyle Upside Down With These 5 "No-Quick-Fix" Tips

It is hard and it takes time, but as long as it's "only" insulin resistance and not full-blown diabetes (=pancreatic failure) most people can get rid of it by turning their lives upside down.

I am sure people are going to misunderstand this, but in the end, insulin resistance was, is and will always be a consequence of "obesity". Maybe not in the way it is currently understood with the BMI determining whether you are "normal" or "obese", but certainly if you define being obese as being fat and storing the most part of the fat in the visceral adipose tissue and the liver.

Thus our definition of what I would like to call "metabolically relevant adiposity" instead of "obesity" can apply to lean and "obese" people alike. In fact, the number of people with a "normal body weight" and insulin resistance is ever increasing. So, if you don't want to be one of them, you better keep the following five DOs and avoid the corresponding "DON'Ts", which would be sitting or lying around all day, eating and drinking sugar-sweetened foods and beverages, consuming alcohol (and other hepatoxic substances), smoking cigarettes, staying up late, eating 24/7, missing your daily time-outs and abusing stimulants.

Details on the optional use supplements & medications will follow next Sunday. What I can already tell you, though, is that can get rid of insulin resistance without a single supplement or pharmacological agent, but you will never get off the diabesity track, if you are unwilling (don't you ever tell me you are "unable") to change the way you eat and increase your daily activity levels.

And yes, lifestyle modification is all it takes for most of us to regain insulin sensitivity and rid ourselves of type II diabetes (in the early stages): With 50% of the subjects being able to normalize their blood glucose levels and more than 50% of the type 2 diabetics in the study being in remission on the follow up, he Malmö study was the first, but is not the only the large scale intervention study that demonstrated the potent anti-diabesity effects of diet and exercise (Eriksson. 1991).

I. Work out anaerobically, aerobically and frequently

Workout evolution: It goes without saying that I don't expect you to start working out 5x per week "cold turkey", i.e. if you have been sitting around 364 out of 365 days of the year for the most part of your previous life (I don't have to repeat that this is over, now, right?). On the other hand, I would be lying if I told you that you can actually make measurable progress without at least 3 workouts per week. I would thus suggest you start with a 2 + 1 strategy using 2 full body workouts and one light intensity cardio training, after a month you add another cardio session and after 3 month you will add in the additional strength training session. After 6 months you switch to a split routine and increase the intensity on your cardio sessions by 15% - this should not feel more intense now that your fitness has improved than the original regimen you've taken up 180days before.

There is nothing that helps your body clean up the mess like working out. Researchers from the University of Verona and Azienda Ospedaliera Universitaria Integrata of Verona have just published a paper on the differential effects of strength and aerobic training on the liver fat content in type 2 diabetic subjects with NAFLD. The results were pretty amazing.

After only 4 months in the course of which the subjects ate according to the (imho not exactly optimal dietary recommendations for type II diabetics; i.e. low fat) and 3 workouts per week, both the subjects in the 3x9 exercise in a circuit training fashion and their peers in the 60min aerobics @ 60-65% of the max. heart rate had lost 32.8% and 25.9% liver fat.

"Additionally, hepatic steatosis (defined as hepatic fat content>5.56%) disappeared in about one-quarter of the patients in each intervention group (23.1% in the AER group and 23.5% in the RES group." (Bacchi. 2013)

While there is no study that measured the effects of training fasted on the liver directly, I guess you can take it for granted that esp. the group doing the aerobics could have improved their results even further, if they had performed their 60min of cardio on empty.

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Bottom line: Get active or stay active. Combine resistance and aerobic training. Get serious and start working your way up to 5 workouts per week with 2x aerobic (steady state walking on an incline treadmill or taking a fast walk for 45min) and 3x resistance training sessions (either a circuit training or a pull, push, legs, 3-way split; don't train to failure in more than one set per exercise, keep the reps in the 8-10 range, increase the weights appropriately, do max. 18 sets per workout, in & out of the gym in <30min) to get rid of your insulin resistance and at least 3 workouts (2x weights, 1x LISS) if you just want to keep your insulin sensitivity is already high and you want it to stay just there.

II. Minimize your sugar intake, control your carb intake

In case you wonder where the 120g come from and if this is just some random number, I suggest you go back to a previous SuppVersity post, namely "Carbohydrate Shortage in Paleo Land: New Data for A Scientific Outlook at the Low-to-No Carb Paleo Confusion. Will More Than 125g of Carbs Make You Fat?", you may also want to reread my interview w/ Sean Casey at CasePerformance.com

Sugar, irrespective of whether its plain table sugar or HFCS is a no-go from now. The same goes for all products that contain significant amounts of it. And no, you are not going to cut back slowly on your Coke, you know that you've failed miserably before and you will fail again. You simply won't buy and drink any sugar containing beverages (including "healthy" juices which have only recently been associated with an almost 25% increased risk of developing type II diabetes) and foods.

At the same time, you will reduce your carbohydrate intake to 120g per day with a 40g limit on a per meal basis. It should not be necessary and may even be detrimental to go further down, because you won't ever learn how to walk without a crutch if you sit in a wheelchair - or to leave the metaphors behind: Unless you intend to stay insulin resistant and metabolically unflexible for the rest of your life, you better not go "no carb", as this will effectively require a high degree of (physiological) insulin resistance to work (for the morbidly obese it may yet be necessary to take the ketogenic route).

Moreover, the "gray area" between 120g and no-carbs sets you up to hypoglycemic episodes as your body will not effectively switch into ketosis, which would be necessary to supply a steady amount of energy. This problem will become even more pronounced, when you try to make up for the lack of carbs by consuming exorbitant amounts of protein.

Unless you are "skinny fat" (normal or low BMI + insulin resistant) you will use the reduction in carb intake to generate a -15% to -20% caloric deficit to shed a couple of pounds of fat weight - and no, this is NOT going to happen without a caloric deficit.

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Bottom line: 120-150g is an amount of carbs you should aim for as an intermediate goal. With <50g of carbs per serving you should be able to handle that without major blood sugar excursions, as long as you stick to your workout regimen and totally cut out processed foods with simple sugars. Also, fructose from whole fruit is not your enemy! You just have to make sure you account for it in your daily carb allowance. The latter is not the case for the minimal amount of carbs in green leafy veggies and co (broccoli, calliflour, zuccini, asparagus etc. you can safely fill yourself up on those)

III. Limit your alcohol intake, quit smoking and avoid medications

Contrary to its name, which is "non-alcoholic fatty liver disease", alcohol, does still play a major role in the etiology of NAFLD. It may not be the sole reason, but the way it inhibits the normal function of your liver makes it more susceptible to the junk-food assaults it's exposed to on an almost daily basis. The same goes for all medications / "supplements" with hepatoxic effects.

Compromised liver health as in beginning or full-blown (N-)AFLD is a totally underestimated risk factor for gyneco- & lipomastia as it hampers the not only the glucose, but also the hormone metabolism in the liver (learn more)

Cigarettes on the other hand may not be directly damaging your live, but they stimulate the central nervous system, promote gluconeogenesis and impair it's shut-down, when your blood sugar is already high, so that your liver will actively and acutely contribute to the deterioration in blood sugar metabolism. At the same time the increased efflux of free fatty acids (FFA) from the adipose tissue to the liver increases your risk of developing NAFLD.

Moreover, nicotine does also increase the chronic mammalian target of rapamycin (mTOR)/p70S6 K activity and insulin receptor substrate-1 (IRS-1) Ser636 phosphorylation and will thus directly promote skeletal muscle insulin resistance (Bajaj. 2012).

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Bottom line: While the chronic ingestion of more than 1 glass of wine per day is going to give you alcoholic liver disease, regular weekend binges precipitate and accelerate the development of NAFLD and insulin resistance. Cigarettes will compromise your insulin sensitivity in multiple ways and the use of medication, let alone performance enhancing drugs with detrimental side effects on the liver will exponentially increase the negative impact of any dietary glitch on your insulin sensitivity.

IV. Sleep, de-stress and control your stimulant intake

Please remember: Sympathetic overtraining from heavy lifting can cause sleeplesness while para-sympathetic overtraining from training too much (you can easily make the transition from sympathetic to parasympathetic overtraining), will leave you exhausted 24/7 - the 5x/week scheme above is only sustainable if you stick to the given volume and intensity limits and light intensity steady state cardio training (if you want on empty early in the morning). The latter is a better complement to restistance training than HIIT for improving insulin resistance because there is less overlap between the metabolic pathways they target).

Not getting enough sleep, alone will hamper you ability to handle glucose. This is mostly due to changes in the hormonal profile with chronically elevated cortisol levels esp. in the evening, a lack of nightly growth hormone stimulation and a desynchronization of the central (brain) and peripheral (liver, muscle, other organs) clock.

Figure 1: After 6 nights with only 4h of sleep (left) your glucose insulin response to breakfast deteriorates compared to 6 nights with 12h spend in bed (not necessarily 12h sleeping; Spiegel. 1999)

Even if you are sleeping enough constant psychological stress will have very similar effects on your insulin sensitivity.

The latter is also true for the use of stimulants. It's scary to see how many of us depend on them to even make it through the day. Aside from circadian shifts, they will have the same detrimental effects on the FFA metabolism and gluconeogensis as cigarette smoking (see discussion under item III).

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Bottom line: Plan your sleep and time-outs across the day as rigorously as your workout & nutrition. Spend 8h in bet every night (if that does not help try 1-10mg of melatonin; learn more). Close the curtains and use ear-plugs if that helps you sleep. Schedule at least 15 minutes of idleness every 3h. That's about as much time as it takes to brew and drink a cup of tea. The emphasis here is on "a" (=a single) cup of tea. If you feel too tired to make it through the day without >400mg of caffeine, this is a clear cut sign you got to revise your sleep & destress routine.

V. Fast, get enough protein and watch your omega-6 intake

US childhood obesity map. Go back to the "Insulin Resitance Saga" to learn about the roots diebesity in the kindergarten.

I am aware that the general advice is different, but if you eat every 1-2 hours even the blood glucose levels of a normal person will hardly ever go back to those levels, where you want them for AMPK to go up and initiate the "decluttering" process in your liver and the rest of your body (learn more).

Also try and to get ~2x the RDA, i.e. 1.6g of protein per kg of body weight from food (learn why) and spread your protein intake across your meals in a way that ensures that you'll get at least 30g or quality protein per meal (find out why this is important). Consider using a protein shake after your resistance training sessions.

If possible include fatty fish in your diet on one, better two days of the week and keep an eye on your overall omega-6 intake. Try to reduce it to achieve a 5:1 omega-6 to omega-3 ratio (or lower; learn why). If you cannot force yourself to eat fish, consume 1-2g of fish oil in capsules every other day.

Too much of a good thing? Micrograph of non-alcoholic fatty liver disease, caused by the same kind of lipid accumulations M-Shirazi et al. observed in rats after receiving high dose fish oil supplements in a 2011 study (learn more)

Don't discard the value of ALA (=short chain omega-3 fatty acids) and don't fool yourself to believe that saturated fats were totally benign. Increased levels of palmitic acid in the hypothalamus and skeletal muscle, for example, are mechanistically linked to local insulin resistance (Benoit. 2009; Hirabara. 2010). Everything in moderation!

In this context it is also worth mentioning that you do not want to totally eliminate omega-6 fatty acids from your diet. A 2012 study by Sawada et al., for example, showed that the allegedly bad arachidonic acid (ARA, the end-product of the enzymatic conversion of short-chain omega-6 fatty acids) is a 75x more potent activator of skeletal muscle glucose uptake than oleic acid and on par with it's omega-3 cousin DHA (Sawada. 2012).

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Bottom line: Don't eat 2h before bed, and / or skip breakfast to extend your daily fasting period to at least 10h, but no more than 16h (you need that 8h window to fit in 2-3 meals). Get enough protein in your diet, but make sure you are not living off protein alone. Try to normalize your omega-6:omega:3 ratio. Strive for an 5:1 ratio of n-6:n-3 or less. Don't be fooled by the "saturated fat is not the problem"-lie and keep in mind that palmitic acid, not arachidonic acid is the bad guy, when it comes to skeletal muscle insulin resistance (things may look different when we are talking about endothelial inflammation, but this guide is about the remission of insulin resistance).

Dont forget to come back next week for Part II of this two part series.

References:

• Bajaj M. Nicotine and insulin resistance: when the smoke clears. Diabetes. 2012 Dec; 61(12):3078-80. 
• Benoit SC, Kemp CJ, Elias CF, Abplanalp W, Herman JP, Migrenne S, Lefevre AL, Cruciani-Guglielmacci C, Magnan C, Yu F, Niswender K, Irani BG, Holland WL, Clegg DJ. Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents. J Clin Invest. 2009 Sep;119(9):2577-89.
• Eriksson KF, Lindgärde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmö feasibility study. Diabetologia. 1991 Dec;34(12):891-8
• Hirabara SM, Curi R, Maechler P. Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cells. J Cell Physiol. 2010 Jan;222(1):187-94.
• Sawada K, Kawabata K, Yamashita T, Kawasaki K, Yamamoto N, Ashida H. Ameliorative effects of polyunsaturated fatty acids against palmitic acid-induced insulin resistance in L6 skeletal muscle cells. Lipids Health Dis. 2012 Mar 12;11:36. 
• M-Shirazi M, Taleban FA, Abadi AR, Sabetkasaei M. Fish oil increases atherosclerosis and hepatic steatosis, although decreases serum cholesterol in Wistar rat. J Res Med Sci. 2011 May;16(5):583-90. PubMed PMID: 22091279; PubMed Central PMCID: PMC3214368.
• Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999 Oct 23;354(9188):1435-9.