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L-Carnitine

  • Cardiovascular disease (CVD) is the most common interference with healthy aging and long life in the modern world. Here are a number of proactive ideas and tips to help you prevent the problems associated with heart disease. The triad of primary risk factors is smoking (nicotine addiction), high blood pressure, and high cholesterol. Even if your parents had high cholesterol or early heart disease, you can override, or at least delay, these influences with a proactive, healthy lifestyle.

    There is a cholesterol controversy between integrative medicine and Western-focused doctors. All believe now that inflammation is the key, and oxidation of cholesterol molecules is really the underlying concern. Most docs believe that statin drugs are the answer to CVD troubles, yet PREVENTION is truly the answer. So, let’s take a look at some ideas and actions for preventing these common problems.

    1. Maintain your ideal weight as closely as possible. If you smoke, do everything in your power to stop.

    2. Minimize your intake of saturated animal fats, especially excessive dairy products, as they seem to raise cholesterol more than other foods. Also avoid hydrogenated oils that clog and stress the cardiovascular system. All of these fats increase both total cholesterol and the harmful form of cholesterol (LDL), especially when oxidized.

    3. Minimize your intake of high-calorie, low-nutrient foods like baked goods, chips, boxed sugared cereals, and other processed foods, as well as the salty snacks from chips to cured meats. These foods contribute to obesity, a leading risk factor for CVD. Avoiding chemical exposure as much as possible will lessen the irritation/inflammation of the blood vessels, believed to be the main starting point of plaque formation and arteriosclerosis of blood vessels, the beginning of cardiovascular disease.

    4. Exercise regularly with a balanced program that includes stretching for flexibility, aerobics for endurance, and weight training for strength. This can help to lower body weight, blood pressure, and cholesterol. Exercise also lowers your harmful cholesterol (LDL) and raises your good cholesterol (HDL). And exercise makes your body, mind, and heart happy.

    5. Eat more high-fiber, high-nutrient, lower-calorie foods, such as vegetables, whole grains, legumes, and fruits. This diet can help you to live longer.

    6. Get good-quality oils by eating nuts and seeds (ideally raw, unsalted, and organic), such as almonds, walnuts, sunflower seeds and pumpkin seeds, as well as omega-3 oily fishes that include salmon and sardines (good with green salads). Use olive oil as your main vegetable and cooking oil.

    7. Nutritional supplements to consider for protection against cardiovascular disease include: antioxidant vitamins C and E, omega-3 fatty acids, and the B vitamins (especially B-6, B-12, B-3, and folic acid) to maintain normal cholesterol metabolism and minimize homocysteine levels.

    8. Special nutrients that can be helpful in preventing and treating early disease include L-carnitine, Co-enzyme Q-10, chromium, and higher levels of niacin, mainly the regular flushing niacin as this may work better to metabolize blood fats, although many people use the non-flushing (but not time-released) inositol hexanicotinate.

    9. Learn to manage your stress, let go of anger and frustrations, and communicate your feelings in a safe and non-aggressive way. Practice forgiveness and moving forward in life, still being aware of what you have learned from your life experiences (to avoid repeating mistakes in behavior).

    10. Develop close personal relationships that you can count on for support. Continue to expand your ability to give and receive in your friendships/loving relationships. Love is healing at many levels.

  • The heart is a functioning muscle and needs oxygen and fuel in order to do its work. It is the job of the coronary arteries to supply the necessary oxygen and nutrients to the muscle. When one of the three major coronary arteries become narrowed or blocked, blood flow to the muscle is reduced, resulting in angina pectoris—a feeling of tightness or pressure in the chest often associated with shortness of breath. At first, angina may only be obvious during periods of exercise or emotional stress, and may go away when the activity ceases. Later, it may occur even while resting. If the blood flow to an area of the heart completely stops, heart muscle cells die, causing a heart attack, or myocardial infarction. While healing, the infarcted or damaged area forms a scar, but is no longer a functioning part of heart muscle.

    Conventional medical treatments for angina include blood vessel dilators such as nitroglycerine and other nitrites and calcium channel blockers. If arteriograms show clogged coronary arteries, bypass surgery is usually recommended.

    Dietary Supplements: Primary Recommendations

    Vitamin C
    Those pesky little free radicals really get around. They seem to be involved in almost every cardiovascular condition, and angina is no exception.1,2 Consequently, it's not surprising that vitamin C and other antioxidants, which neutralize free radicals, are beneficial in the prevention and treatment of angina. In fact, studies have shown that men and women with lower blood levels of vitamin C have a higher risk for angina.3,4,5,6 Furthermore, research has also shown that vitamin C supplementation, with or without other antioxidants, has been able to reduce the incidence of angina.7,8,9 About 2,000 mg of vitamin C daily is recommended.

    Co-enzyme Q10
    Co-enzyme Q10 is a vitamin-like substance involved in cellular energy metabolism. It is also an antioxidant, like vitamin C, that is beneficial in the prevention and treatment of angina. In a study, which reviewed the scientific literature, Co-enzyme Q10 was revealed to be used in oral form to treat various cardiovascular disorders including angina.10 In one study, patients with acute myocardial infarction experienced a significant reduction in angina, arrhythmias (abnormal heartbeat), and poor heart function when supplemented with 120 mg of Co-enzyme Q10 daily.11 Of course everyone knows that exercise is good to prevent cardiovascular disease. But in one study, patients with ischemic heart disease/effort angina were found to experience a faster loss of Co-enzyme Q10 during exercise.12 Does this mean that you shouldn't exercise if you have angina? No, it just means you should supplement with Co-enzyme Q10. In another study, 150 mg of Co-enzyme Q10 given to angina patients not only increased their blood levels of Co-enzyme Q10, but also increased their ability to exercise longer. These results lead the researchers to conclude, "This study suggests that Co-enzyme Q10 is a safe and promising treatment for angina pectoris."13 (Note: If you have acute angina, you should only exercise in accordance to a program approved by your physician.)

    Vitamin E
    Vitamin E is considered by many to be the granddaddy of all antioxidant and cardiovascular support vitamins—and this reputation certainly holds true in the case of angina. As with vitamin C and Co-enzyme Q10 previously discussed, vitamin E protects against the free radical damage associated with angina. But what happens when there are inadequate levels of vitamin E? Not surprisingly, research shows that blood levels of vitamin E are significantly lower in patients with angina, and that these lower levels render them more susceptible to further cardiovascular damage.14,15,16 And what happens if vitamin E is supplemented? Various studies show that vitamin E supplementation, with or without other antioxidants, is able to successfully decrease the incidence of angina in affected patients.17,18,19 In fact, in a study, which examined vitamin use in 2313 men, vitamin E supplementation was found to have the strongest association with a reduced risk of ischemic heart disease, including angina.20 Finally, vitamin E supplementation together with conventional anti-anginal drug therapy has been found to bring a higher response and exercise improvement, as well as other positive changes, than drug therapy alone.21 About 100 –400 IU of vitamin E daily is recommended.

    L-Carnitine
    L-carnitine is an amino acid involved in energy metabolism. Extensive research has also shown that l-carnitine has a valuable role to play in cardiovascular disease, especially where angina is concerned. Several studies have demonstrated that supplementation with l-carnitine (2000 to 4000 mg daily) is able to reduce the incidence of anginal attacks in cardiovascular disease patients.22,23,24,25 Furthermore, in studies involving patients with angina pectoris and effort angina (i.e., angina induced by physical effort, such as exercise), supplementation with l-carnitine (2000 or 3000 mg daily) was able to improve exercise performance.26,27,28,29,30 Furthermore, in a study where l-carnitine was given to patients with effort angina along with anti-arrhythmic drugs, the l-carnitine was found to improve the action of those drugs.31

    Hawthorne
    Germany's Commission E has validated the use of Hawthorn in cases of cardiac insufficiency, resulted in an improvement of subjective findings as well as an increase in heart work tolerance, and a decrease in pressure/heart rate product.32 (Although Hawthorne Berry products are often marketed, it is the Hawthorne leaves and flowers which have been so carefully researched and validated.). In one study, a 60 mg hawthorn extract taken three times per day improved heart function and exercise tolerance in angina patients.33

    L-Arginine
    Typically physicians will give their angina patients a prescription for nitroglycerin tablets, which are used in case of an angina attack. Nitroglycerine works through dilation of arteries, which in turn, works through an interaction with nitric oxide, which stimulates dilation. It is interesting to note that nitric oxide is made from the amino acid arginine. Furthermore, blood cells in people with angina have been shown to make insufficient nitric oxide,34 (possibly due to abnormalities of arginine metabolism). Of greatest significance is research showing that 2 grams (2,000 mg) of arginine, three times per day for as little as three days improved the ability of angina sufferers to exercise.35 Additional research has shown that the mechanism by which arginine operates is through stimulating blood vessel dilation.36 (Note: If you have an active herpes virus, you should avoid arginine supplements since they can "feed" the virus.)

    Dietary Supplements: Secondary Recommendations

    Magnesium
    The heartbeat normalizing effects of magnesium has been described repeatedly since 1935, both as a factor in human disease and in animal experiments. Nevertheless, this therapeutic effectiveness is rarely mentioned in textbooks. Both the therapeutic effect of magnesium and the correction of magnesium deficiency have been used in treatment of digitalis toxicity (a drug used to treat angina), angina, as well as in arrhythmia (abnormal heartbeat) of unknown origin. Magnesium deficiency can be caused by a number of situations. Of possible concern to the angina sufferer are the uses of drugs such as digitalis, diuretics, gentamicin, as well as cisplatinum, which appreciably enhance urinary magnesium loss. Correction of magnesium deficiency should lead to recovery.37 About 300 – 500 mg daily is recommended. Please note, however, that it may take weeks or even months of magnesium supplementation, to achieve an angina-relieving result.

    Omega-3 fatty acids
    The omega-3 fatty acids EPA and DHA have been studied in the treatment of angina. Some research indicates that 3 grams or more of omega-3 oils (e.g., fish oils) three times per day (providing a total of about 3 grams of EPA and 2 grams of DHA) have reduced chest pain as well as the need for nitroglycerin, a common medication used to treat angina.38 However, other research did not confirm these benefits.39 In any case, if omega-3's are used, vitamin E should be supplemented with it, since the vitamin E may protect the oils against free radical oxidation.40 Also, if you are using any type of blood-thinning medication, consult with your doctor before using omega-3 fatty acids.

    Bromelain
    Bromelain acts naturally as a blood thinner agent since it prevents excessive blood platelet from clumping together,41 which would otherwise cause "sludgy" blood. Furthermore, there have been positive reports in a few clinical trials of bromelain to decrease thrombophlebitis (inflammation of veins) and pain from angina and thrombophlebitis.42,43 About 1200–1500 mg daily (derived from at least 900 GDU/Gram material) is recommended.

    References:

    1. Ito K, et al, Am J Cardiol(1998) 82 (6):762-7.
    2. Kugiyama K , et al, J Am Coll Cardiol (1998) 32(1):103–9.
    3. Ibid.
    4. Riemersma RA, et al, Ann NY Acad Sci (1989) 570:29–5.
    5. Riemersma RA, et al, Lancet (1991) 337(8732):1–5.
    6. Ness AR, et al, J Cardiovasc Risk (1996) 3(4):373–7.
    7. Ito K, et al, Am J Cardiol (1998) 82 (6):762–7.
    8. Kugiyama K, et al, J Am Coll Cardiol (1998) 32(1):103–9.
    9. Singh RB, et al, Am J Cardiol (1996) 77(4):232–6.
    10. Greenberg S, Frishman WH, J Clin Pharmacol (1990)30(7):596–608.
    11. Singh RB, et al, Cardiovasc Drugs Ther (1998) 12(4):347–53.
    12. Karlsson J, et al, Ann Med (1991) 23(3):339–44.
    13. Kamikawa T, Am J Cardiol (1985) 56 (4):247–51.
    14. Miwa K, et al, Cardiovasc Res (1999) 41(1):291–8.
    15. Miwa K, et al, Circulation (1996) 94(1):14–8.
    16. Pucheu S, et al, Free Radic Biol Med (1995) 19(6):873–81.
    17. Rapola JM, et al, JAMA(1996) 275(9):693–8.
    18. Singh RB, et al, Am J Cardiol (1996) 77(4):232–6.
    19. Motoyama T, et al, J Am Coll Cardiol (1998) 32(6):1672–9.
    20. Meyer F, Bairati I, Dagenais GR, Can J Cardiol (1996)12(10):930–4.
    21. Pimenov LT, Churshin AD, Ezhov AV, Klin Med (1997) 75(1):32–5.
    22. Singh RB, et al, Postgrad Med J (1996) 72(843):45–50.
    23. Davini P, et al, Drugs Exp Clin Res (1992) 18(8):355–65.
    24. Fernandez C, Proto C, Clin Ter (1992) 140(4):353–77.
    25. Ferrari R, Cucchini F, Visioli O, Int J Cardiol (1984) 5(2):213–6.
    26. Kobayashi A, Masumura Y, Yamazaki N, Jpn Circ J (1992) 56(1):86–94.
    27. Cacciatore L, et al, Drugs Exp Clin Res (1991) 17(4):225–35.
    28. Canale C, et al, Int J Clin Pharmacol Ther Toxicol(1988) 26(4):221–4.
    29. Cherchi A, et al, Int J Clin Pharmacol Ther Toxicol (1985) 23(10):569–72.
    30. Kamikawa T, et al, Jpn Heart J (1984) 25(4):587–97.
    31. Mondillo S, et al, Clin Ter (1995) 146(12):769–74.
    32. Blumenthal, M., et al, The Complete German Commission E Monogrpahs: Therapeutic Guide to Herbal Medicines/CD version (1998) American Botanical Council, Austin, Texas.
    33. Hanack T, Bruckel MH, Therapiewoche (983) 33:4331–33 [in German].
    34. Mollace V, et al, Am J Cardiol (1994) 74:65–68.
    35. Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K, Am J Cardiol (1997) 80:331–33.
    36. Egashira K, et al, Circulation (1996) 94:130–34.
    37. Laban E, Charbon GA, J Am Coll Nutr (1986) 5(6):521–32.
    38. Saynor R, Verel D, Gillott T, Atheroscl (1984) 50:3–10.
    39. Mehta JL, et al, Am J Med (1988) 84:45–52.
    40. Wander RC, et al, J Nutr (1996) 126:643–52.
    41. Heinicke R, van der Wal L, Yokoyama M, Experientia (1972) 28:844–45.
    42. Nieper HA, Acta Med Empirica (1978) 5:274–78.
    43. Seligman B, Angiology (1969) 20:22–26.
  • The nutrients L-carnitine and choline are two of the most important for heart and liver health. Large bodies of literature support the benefits of these compounds and that of related items, such as phosphatidylcholine. Despite this history, recently news media articles have appeared suggesting that these nutrients actually cause heart disease. Similarly, in the medical professional research literature, there is a groundswell of publications that attempt to associate L-carnitine and choline with cardiovascular disease through entirely indirect arguments involving primarily the compound trimethylamine-N-oxide.

    In a nutshell, these publications cast aside direct clinical evidence that supplementing with L-carnitine and choline improves heart and liver health by focusing, instead, on marker compounds in the blood and correlations between these and illness without establishing causation. The presence of a biochemical marker is used to overturn clinical evidence such that compounds proven in practice to be good for health suddenly are associated with disease. As argued in the following paragraphs, this guilt by association does not withstand close scrutiny.

    L-Carnitine and Choline

    Although the L-carnitine is usually referred to as an amino acid, this is technically incorrect inasmuch as there is no amino (NH2) group present in the molecule. The primary role of L-carnitine in the body is as a biocatalyst or coenzyme. One of the most important functions of L-carnitine is in the oxidation of long chain fatty acids, a process which takes place inside of mitochondria, the “energy factories” of the cells. This process is known as beta-oxidation. L-Carnitine acts as a shuttle for bringing fatty acids into the mitochondria and then removing waste afterwards. Fats are the preferred source of fuel for the kidneys, the skeletal muscles, and even more so for the heart muscle. As much as 70 percent of the energy generated in muscle tissue comes from the oxidation of fats!

    L-Carnitine also increases the rate of oxidation of fats in the liver, and this suggests that it plays a role in energy generation from this angle as well.1 Some authors argue that in the proper amounts, L-carnitine supplementation during dieting can help to control the negative effects of ketosis (the accumulation of waste products of fat metabolism) in those who are susceptible to this problem.2 Similarly, there is evidence that some forms of obesity may be related to a genetic propensity to produce less L-carnitine, and liver and kidney problems will reduce the body’s production since some four fifth’s of our total L-carnitine is produced internally by these organs.3,4

    L-Carnitine has been shown to have positive benefits upon the myocardium of the heart and upon peripheral circulation. The effects upon the heart include improvements in energy production and other parameters. Supplemental L-carnitine is associated with significantly higher concentrations of pyruvate, ATP and creatine phosphate in portions of the heart muscle during conditions of extreme stress.5 Similarly, in tests upon peripheral circulation, L-carnitine has been found to be quite useful for improving blood flow.6 Of course, the true test of the benefits of L-carnitine is survival: In a randomized controlled trial, there was a 90 percent decrease in mortality over the next 12 months compared with people who did not receive L-carnitine when patients started supplementing shortly after suffering a heart attack.7 Another study analyzing 13 controlled trials (involving a variety of settings) found that L-carnitine led to a 27 percent reduction in all-cause mortality.8 Choline, phosphatidylcholine and related compounds are especially protective of liver health, including in both nonalcoholic and alcoholic fatty liver disease.9,10 Liver dysfunction is extremely common in those who carry excessive weight and is viewed as causative in diabetes type 2. L-Carnitine and choline reduce overall oxidative stress in individuals and lower lipid peroxidation, recognized factors in promoting cardiovascular and liver health.11

    L-Carnitine Slows Plaque Formation in Arteries Despite TMAO
    A paper published in the journal Atherosclerosis (2016) reconfirms some of the health benefits of L-carnitine and, by implication, those of choline, phosphatidylcholine and related nutrients. In a nutshell, researchers fed supplemental L-carnitine to mice for 12 weeks and then observed aortic lesion development and blood lipid profiles. These scientists wanted to test the truth of a vast body of older science that demonstrated the cardioprotective properties of L-carnitine versus new theories that gut microbes transform L-carnitine into trimethylamine (TMA) that the liver further transforms into trimethylamine-N-oxide (TMAO) that promotes atherosclerosis. The researchers found that L-carnitine supplementation slows aortic lesion formation in their mouse model. L-Carnitine was heart protective just as indicated in previous research based on examining clinical results rather than looking only at short term markers purported to indicate future results (endpoints versus markers). Moreover, TMAO, the supposedly toxic metabolite of L-carnitine, actually appeared to protect the arteries. One implication of this study is that L-carnitine, including its metabolite TMAO, may be similarly protective against atherosclerosis development in humans.

    Study Summary
    The current study was designed to test the hypothesis of an article published in Nature Medicine (2013) that suggested that the nutrient L-carnitine, found in red meat and nutritional supplements, promotes atherosclerosis as a result of bacteria in the gut forming a toxin called trimethylamine (TMA), which is further metabolized in the liver to trimethylamine-Noxide (TMAO).13 Two follow-up articles by many of the same Nature Medicine authors argue that gut bacteria similarly transform dietary betaine, choline and phosphatidylcholine (and presumably other choline-related nutrients) to yield TMA followed by TMAO with negative cardiovascular consequences. Since the initial publications, there has been a flood of research putatively supporting the original findings. Inasmuch as TMAO plasma levels have been associated with atherosclerosis development in the particular mouse model used in the initial research, the goal was to better understand the mechanisms behind the TMAO/CVD association. The Atherosclerosis (2016) research was designed to investigate both in vitro (isolated cell or tissue) mechanisms—does TMAO promote foam cells formation—and in vivo (live animal) endpoints—does TMAO promote or inhibit lesion development in the arteries.

    The in vitro part of the study demonstrated that TMAO at concentrations up to ten times the maximum reported in humans did not affect foam cell formation. In other words, there was no indication that a mechanism exists through which TMAO causes damage to the lining of the arteries. However, there still were outstanding issues, such as why TMAO was both elevated in the usual mouse model and linked to increased levels of atherosclerosis.

    The in vivo part of the study provides important answers to these issues. First, it must be understood that rodents in general process lipids, including cholesterol, differently than do humans. For instance, the usual mouse model for atherosclerosis lacks cholesteryl ester transfer protein (hCETP), which in humans is involved in the movement of cholesterol between high density lipoprotein (HDL) and low density lipoprotein cholesterol (LDL). Using a model that more properly matches human lipid metabolism, high doses of L-carnitine resulted in a significant increase in plasma TMAO levels, yet—and regardless of treatment—TMAO levels were inversely correlated with aortic lesion size. Indeed, as the blood levels of TMAO went up, the size of the aortic lesion area went down and this bore no relation to changes in blood lipids. One clear implication of these findings is just the opposite of that commonly being suggested regarding TMAO, to wit, TMAO is protective of arterial health rather than being a toxin.

    So What Goes Wrong in Humans to Elevate TMAO?
    There is little doubt that ingestion of L-carnitine, betaine, choline and related nutrients can increase TMAO levels in many individuals and that increased TMAO also can be associated in many cases with increased cardiovascular disease. However, it is becoming increasingly clear that TMAO is not a cause of atherosclerosis.

    Study after study after study that has looked at clinical endpoints, meaning the actual outcomes of the use of L-carnitine with human beings, has shown significant benefits across a wide array of heart and circulatory issues.14 Benefits are found with choline, phosphatidylcholine and related nutrients along with eating oily fish, a practice that necessarily dramatically increases TMAO, yet supports good health.

    This is a classic case of blaming a messenger for the message. Just as with TMAO, elevated blood levels of choline sometimes are seen in patients with artery plaque instability, but this is a result of the instability itself and is unrelated to supplements just as an analogously disturbed L-carnitine regulation arguably is a result of cardiovascular problems and not due to dietary intake.15,16 In a clinical trial, oral L-carnitine supplementation increased trimethylamine-N-oxide, but reduced indications of vascular injury in hemodialysis patients.17 Elevated TMAO blood levels are associated with low HDL and related disturbances just as elevated TMAO levels appear to be linked to impaired kidney function and poor metabolic control.18,19 The clear implication is that TMAO levels may reveal problems that originate elsewhere in the body and that artificially lowering TMAO blood levels will not improve health because TMAO is not the cause of these issues. The key concept here is to look at "endpoints," not "markers."

    Food Sources
    Meat, poultry, fish, and dairy products are the richest food sources of L-carnitine, although L-carnitine intake probably is increased best via supplements. This route is not so necessary for betaine, choline and a number of related nutrients. According to the Linus Pauling Institute, the consumption of choline is far below the recommended intake in the United States. Rich sources of choline include eggs, liver, wheat germ, many types of seafood and even peanuts. According to Whole Foods, vegetable options include collard greens, Brussels sprouts, broccoli, Swiss chard, cauliflower, and asparagus. A large listing of food sources can be found at http://nutritiondata.self.com/. Many choline sources also are good sources of phosphatidylcholine (liver, egg yolk, peanuts). Choline's metabolite betaine can be found in spinach, beets and shellfish.

    Endnotes

    1. Preuss HG, Mrvichin N, Clouatre D, et al. Importance of Fasting Blood Glucose in Screening/Tracking Overall Health. The Original Internist. 2016, March:13¡V15,17¡V18.
    2. Bjornholt JV, Erikssen G, Aaser E, et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care. 1999 Jan;22(1):45¡V9.
    3. Sears B. Anti-inflammatory Diets. J Am Coll Nutr. 2015;34 Suppl 1:14¡V21.
    4. Mauro DiPasquale, M.D., "Let the Fat be with You: The Ultimate High-Fat Diet," Muscle Magazine International (July and September 1992); "High Fat, High Protein, Low Carbohydrate Diet: Part I," Drugs in Sports 1, 4 (December 1992) 8¡V9.
    5. https://bengreenfieldfitness.com/2015/12/how-to-get-into-ketosis/
    6. Ishihara K, Oyaizu S, Onuki K, Lim K, Fushiki T. Chronic (-)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr. 2000 Dec;130(12):2990¡V5.
    7. Lim K, Ryu S, Suh H, Ishihara K, Fushiki T. (-)-Hydroxycitrate ingestion and endurance exercise performance. J Nutr Sci Vitaminol (Tokyo). 2005 Feb;51(1):1¡V7.
    8. Cheng IS, Huang SW, Lu HC, Wu CL, Chu YC, Lee SD, Huang CY, Kuo CH. Oral hydroxycitrate supplementation enhances glycogen synthesis in exercised human skeletal muscle. Br J Nutr. 2012 Apr;107(7):1048¡V55.
    9. Louter-van de Haar J, Wielinga PY, Scheurink AJ, Nieuwenhuizen AG. Comparison of the effects of three different (¡V)-hydroxycitric acid preparations on food intake in rats. Nutr Metab (Lond). 2005 Sep 13;2(1):23. See also notes 18 and 19.
    10. Clouatre D, Talpur N, Talpur F, Echard B, Preuss H. Comparing metabolic and inflammatory parameters among rats consuming different forms of hydroxycitrate. Journal of the American College of Nutrition 2005;24:429 Abstract.
    11. Clouatre D, Preuss HG. Potassium Magnesium Hydroxycitrate at Physiologic Levels Influences Various Metabolic Parameters and Inflammation in Rats. Current Topics in Nutraceutical Research 2008;6(4): 201¡V10.
    12. Han N, Li L, Peng M, Ma H. (-)-Hydroxycitric Acid Nourishes Protein Synthesis via Altering Metabolic Directions of Amino Acids in Male Rats. Phytother Res. 2016 May 4. doi: 10.1002/ptr.5630. [Epub ahead of print]
    13. http://www.totalhealthmagazine.com/Vitamins-and-Supplements/Going-WILD-with-Bitter-Melon-for-Blood-Sugar-Support.html
    14. Lim JS, Adachi Y, Takahashi Y, Ide T. Comparative analysis of sesame lignans (sesamin and sesamolin) in affecting hepatic fatty acid metabolism in rats. Br J Nutr. 2007 Jan;97(1):85¡V95.
    15. Ide T, Lim JS, Odbayar TO, Nakashima Y. Comparative study of sesame lignans (sesamin, episesamin and sesamolin) affecting gene expression profile and fatty acid oxidation in rat liver. J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):31¡V43.
    16. Henry-Vitrac C, Ibarra A, Roller M, Merillon JM, Vitrac X. Contribution of chlorogenic acids to the inhibition of human hepatic glucose-6-phosphatase activity in vitro by Svetol, a standardized decaffeinated green coffee extract. J Agric Food Chem. 2010 Apr 14;58(7):4141¡V4.
    17. Bassoli BK, Cassolla P, Borba-Murad GR, et al. Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia. Cell Biochem Funct. 2008 Apr;26(3):320 ¡V8.
    18. Malmsten C, Lignell A. Dietary Supplementation with Astaxanthin- Rich Algal Meal Improves Strength Endurance; A Double Blind Placebo Controlled Study on Male Students. Carotenoid Science. 2008;13:20 ¡V22.
    19. Aoi W, Naito Y, Takanami Y, Ishii T, Kawai Y, Akagiri S, Kato Y, Osawa T, Yoshikawa T. Astaxanthin improves muscle lipid metabolism in exercise via inhibitory effect of oxidative CPT I modification. Biochem Biophys Res Commun. 2008 Feb 22;366(4):892¡V7.
  • For Sports and Health

    Most readers who have heard of ketosis and ketogenesis likely associate the concepts with dieting and the works of Dr. Robert C. Atkins (Dr. Atkins’ Health Revolution, 1989; Dr. Atkins’ New Diet Revolution, 1992) that launched a bit of a movement in the 1990s. Much less well known is the role of ketosis in sports and the importance of being able to enter ketosis as an aspect of metabolic flexibility, meaning the ability to rapidly and easily shift between carbohydrates and fats as fuel substrates to match, on the one hand, dietary sources of calories and, on the other hand, particular physical demands for energy. In fact, the health implications of metabolic flexibility are significant and are related to the body’s degree of insulin sensitivity and thereby to the components of the metabolic syndrome. The latter condition often is defined as being based on insulin resistance and associated with abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low high-density lipoprotein (HDL) levels. This way of looking at matters makes ketogenesis and metabolic flexibility major determinants of health. One does not need to be diabetic or even pre-diabetic for these issues to be important, a point that Harry Preuss, MD and various coauthors, including myself, make in a recent article intended for practicing physicians, “Importance of Fasting Blood Glucose in Screening/Tracking Overall Health.”1,2

    Not only athletes for reasons having to do with competition, but also non-athletes for reasons of health likely would benefit from some form of supplement protocol or other approach that can achieve ketogenesis and maintain metabolic flexibility without depending entirely on the diet. Indeed, achieving ketosis via diet alone is hard to maintain over the long haul for a variety of reasons. Eating mostly protein and fat may sound like a treat at the beginning, but highly restricting all sources of carbohydrates quickly leads to a boring diet and even limited social interaction because few social events are built around ketogenic snacks! It also means avoiding many or most sources of phytonutrients, not eating adequate fiber for gut health and bowel regularity, probably inadequately eliminating toxins via the bile route in the stool, and even ramping up production of the hormone cortisol.3 Extreme ketosis leads to unpleasant breath (acetone breath) although this is not an issue with moderate and healthy ketogenesis.

    Background on Ketosis and Ketogenic Diets
    There are only two primary sources of energy, carbohydrates and fats. If needed for energy, protein can be broken down to yield a carbohydrate component, not a fatty acid component. Ketosis refers to the state in which the body meets its energy requirements largely through the oxidation of ketone bodies. These build up in the blood when glucose is not being used for energy and even the brain can run on ketone bodies. Glycolysis is the opposite number to ketosis in that it refers to the oxidation of glucose, for which all carbohydrates ultimately are a source, for energy. People sometimes associate ketosis with diabetes, but ketosis is a nutritional process whereas in diabetes the body either lacks sufficient insulin or cannot respond properly to insulin and therefore builds up ketone bodies due to a failure of metabolism while at the same time not properly harnessing fats for fuel. There is plenty of evidence to the effect that ketogenic diets can be healthful. Traditional Eskimo diets consisted almost entirely of raw meat and blubber (fat) and yet the Eskimos did not exhibit diabetes. Similarly, for certain neurologic conditions children are raised from early life into their thirties or later with completely normal physiologic and mental development without eating any carbohydrates at all.

    Athletes and some "paleodieters" speak of keto-adaptation, which means simply moving the metabolism to preferentially accessing stored fats as fuel sources rather than depending on glucose. The body has quite limited stores of glycogen or "animal starch" stored primarily in the liver in contrast to virtually unlimited calories stored as fats. A quite standard assessment is that there may be 400 grams of glycogen in the liver and another 100 grams in the muscles. Glycogen is associated with water on a 1:3 to 1:4 ratio. A major problem in achieving keto-adaptation by diet alone is that most individuals who have been raised on Western-style diets can take six months or more to make the shift and this shift becomes ever more difficult as we age. Studies examining the role of carbohydrates in the metabolism with roughly 30 year old males in good physical condition have revealed, for instance, that even transitioning from a high glycemic index diet to a low glycemic index diet while maintaining the same ratio of carbohydrate, fat and protein can take more than four weeks. Shifting to fatty acid metabolism for energy can be difficult.

    High fat diets were employed at the turn of the century to treat Type I diabetes, the form that begins in childhood with the destruction of the insulin-producing cells of the pancreas. Since the body can and will produce its own blood sugar from protein in order to feed the brain, there is always some role for insulin in the body regardless of the diet followed. Needless to say, those with juvenile diabetes almost invariably died young until the discovery of insulin.

    In adult-onset or Type II diabetes, which typically begins fairly late in life and with those already overweight, diet and exercise often can completely control the problem. This and other clues have led a number of researchers to suspect that excess weight gain is related to insulin production either directly or indirectly, as discussed briefly above. Dr. Robert C. Atkins was one of the first to popularize the notion of dieting by bypassing the insulin mechanism through eliminating most carbohydrates from the diet while continuing to consume both proteins and fats. Atkins' Diet is both high in protein and high in fat.

    High protein, low fat/very low carbohydrate diets have been common for some time, but not with the particular justification that they bypass the insulin mechanism. Generally the justifications have had to do with energy production, or rather the lack of it on these diets. In the Stillman Diet, for instance, it was argued that protein molecules are so large that they use up extra energy as a food for the body. This diet calls for the drinking of at least eight glasses of water a day, which truly is necessary to remove the waste products of excess protein consumption and from the oxidation of the body's own fats.

    Very similar is the famous Scarsdale Diet, designed for use for only two weeks at a time. Both strictly limit carbohydrates and, somewhat less strictly, fats. Both do reduce weight in the short term, but such large amounts of protein are hard on the body. In contrast to these, the Dr. Atkins' Diet allows for unlimited amounts of both proteins and fats, but for restricted amounts of carbohydrates according to the theory that a faulty insulin mechanism is the cause of excess weight. A more limited form of this ketone-based diet popularized at about the same time as the Atkins Diet is presented by Dr. Calvin Ezrin in The Endocrine Control Diet (1990).

    Athletes long have experimented with ketogenic diets. For instance, during the 1990s a number of top bodybuilders in the World Bodybuilding Federation adopted a diet similar to the one Atkins uses (roughly 40 percent of calories from protein and 60 percent from fat) in order to cut body fat and build muscle. These individuals were all undertaking extremely hard physical labor, so the diet itself cannot be a source of fatigue, but must in fact supply considerable energy.4 Nevertheless, even major competition class athletes ultimately generally give up on strict ketogenic diets. As admitted by Ben Greenfield, a serious triathlete who was tested with regard to the ergogenic benefits of a ketogenic diet, "after the study at University of Connecticut, I personally quit messing around with ketosis and returned to what I considered to be a more sane macronutrient intake of 50-60% fat, 20-30% protein, 10-30% carbohydrate."5

    Ketogenesis with Supplements
    Can ketogenesis be achieved using a more normal diet with the help of supplements? The answer appears to be "yes." Nevertheless, there are important considerations, among which are the following:

    • The diet should not be high in simple sugars, fructose or refined carbohydrates. For non-athletes and those looking primarily to increase metabolic flexibility, the diet should resemble a modified Sears Diet, meaning approximately 20¨C 30 percent protein, 30¨C40 percent carbohydrate and 30¨C40 percent fat. For athletes and individuals who seriously want to initiate and maintain a fat-adapted diet, Ben Greenfield's suggestion is more in order: "50-60% fat, 20-30% protein, 10- 30% carbohydrate."
    • It is helpful to support fat metabolism directly such as through improved transport of fatty acids into the mitochondria for oxidation.
    • Insulin sensitivity must be improved and maintained and insulin levels kept low.
    • The release of fatty acids from fat cells likely is less important than is disinhibiting fatty acid metabolism. The first is accomplished with caffeine, yet often with a downside such as increased cortisol levels, hence alternatives to caffeine and other similar stimulants are needed.
    • Inclusion of substances that actively promote fatty acid oxidation is important to help kick-start the body's ability to metabolize fats.
    • Excessive gluconeogenesis by the liver (creation of glucose from glycogen in response to the release of glucagon) should be inhibited to promote fatty acid oxidation as the alternative.
    • With diets that are heavy in alcohol and fat, potential "reverse" effects must be prevented.

    A small number of supplements, especially if taken together, may fulfill the above requirements and actually have been tested successfully in a pilot case. The subject in question was able to consume a normal diet, indeed one that included quite a bit of alcohol, by relying on only four supplements to remain in moderate ketosis during much of the day: hydroxycitric acid, wild bitter melon extract, sesame lignan extract and green coffee bean extract. The sources of these supplements were not generic and this should be kept in mind because different production methods lead to different products with different results. Published comparative trials, for example, with hydroxycitric acid have shown this definitively.

    Potassium-Magnesium Hydroxycitrate
    The key component in supplement-support ketogenesis is (-)¨Chydroxycitric acid (HCA). That some forms of properly manufactured HCA can be used to encourage ketogenesis has been known at least since 2000. In that year, Ishihara published that HCA ingestion for 13 days increased fat oxidation and improved endurance exercise time to fatigue by 43 percent compared to a placebo in mice.6 Over the following few years, three studies by Lim and others in trained athletes demonstrated that ingestion of HCA enhances endurance performance via increasing fat oxidation and sparing glycogen utilization during moderate intensity exercise. In fact, in trained athletes HCA ingestion for five days shifted fuel selection to fat oxidation at both 60 percent and 80 percent VO2max during exercise.7 Lim further demonstrated a number of significant findings. First, using mice as his model, he showed that chronic HCA ingestion alters fuel selection rather than the simple release of fat from stores as is true of lipolysis, i.e., mechanism for HCA is not the same as with caffeine, capsaicin, etc. Second, Lim's review data that showed that the combination of HCA plus L-carnitine improves glycogen status in liver and various muscle tissues versus placebo in exercised-trained rodents. Since the publication of Lim's papers, this finding has been repeated more than once with human athletes. Although L-carnitine improves the effect, it is not necessary.8 Third, Lim in his studies employed a pure synthesized trisodium hydroxycitrate salt rather than commercial calcium or calcium-potassium HCA salts, which did not yield his results. As is true of many herbal products, the benefits of HCA are highly dependent upon how the item is prepared. The acid must be stabilized by the addition of high pH ions (basic or alkali), such as those of potassium, magnesium or calcium. Using the wrong stabilizing counter-ions results in little or no activity. In the case of the acid derived from Garcinia cambogia and related sources, adding any calcium at all reduces some desired benefits and blocks other benefits entirely.9 This fact has been verified by more than one comparative trial.

    Another benefit of HCA that supports ketogenesis is its impact on insulin sensitivity. At the 2005 Annual Meeting of the American College of Nutrition for the first time it was reported that the potassium-magnesium HCA salt in an animal model gave the same blood glucose regulation as found in the control arm of the test while almost literally cutting insulin levels in half.10 The same study demonstrated that this salt dramatically improved glucose clearance from the blood, lowered systolic blood pressure and also lowered several key indicators of inflammation, including C-reactive protein and tumor necrosis factor-alpha (TNF-alpha). In contrast, the potassium-calcium salt exerted no effect upon insulin and blood sugar regulation and only very poorly influenced blood pressure.11 In the areas of insulin metabolism, glucose regulation and blood pressure, the proprietary potassium-magnesium salt was between five and seven times as active as the potassium-calcium salt of the fruit acid. A paper just published this year also indicates that HCA may help to regulate thyroid hormones and promote muscle protein synthesis.12

    Wild Bitter Melon Extract and Sesame Lignan Extract
    As indicated above, HCA appears to be extremely useful in freeing the body's metabolism regulators to allow a shift towards preferentially oxidizing fatty acids for energy. Increasing insulin sensitivity and reducing insulin levels removes one of the primary brakes on fatty acid metabolism. A complement to these actions is direct activation of fatty acid oxidation. Both wild bitter melon and sesame seed lignans help to do just this. Bitter melon previously has been discussed in these pages under the title, "Going WILD with Bitter Melon for Blood Sugar Support."13 As noted in that article, it has been found that extracts of bitter gourd activate cellular machinery to regulate energy production (technically, AMP-activated protein kinase or AMPK) and the way that fats are handled by the liver. These components can account for as much as 7.1 g/ kg of the dried wild material.

    The sesamolin lignan found in sesame seeds (but not in most extracts) likewise increases fat metabolism. As pointed out in an important study, the "[e]ffects of sesamin and sesamolin (sesame lignans) on hepatic fatty acid metabolism were compared in rats. Sesamolin rather than sesamin can account for the potent physiological effect of sesame seeds in increasing hepatic fatty acid oxidation observed previously. Differences in bioavailability may contribute to the divergent effects of sesamin and sesamolin on hepatic fatty acid oxidation. Sesamin compared to sesamolin was more effective in reducing serum and liver lipid levels [with]sesamolin more strongly increasing hepatic fatty acid oxidation." "Sesamolin rather than sesamin can account for the potent physiological effect of sesame seeds in increasing hepatic fatty acid oxidation observed previously."14 "...gene expression of hepatic enzymes involved in fatty acid oxidation [was] much stronger with episesamin and sesamolin than with sesamin¡­[serum] half lives of 4.7±0.2, 6.1±0.3 and 7.1±0.4 h for sesamin, espisesamin and sesamolin, respectively...15

    Green Coffee Bean Extract
    After meals, up to 70 percent of the glucose from food is stored in muscle and other lean tissues. However, moment-to-moment regulation of blood glucose typically is handled by the liver. It does this via two processes, both of which are highly regulated. Gluconeogenesis generates glucose from certain noncarbohydrate carbon substrates, including certain amino acids and lipid components, such as triglycerides. Glycogenolysis is the freeing of glucose from glycogen stores. In the liver, but not the muscles, the hormone glucagon is involved. The liver also uses the enzyme glucose-6-phosphatase. With aging and as the metabolic syndrome develops, regulation of these two processes becomes impaired. Dysregulation is a particularly significant issue in diabetes.

    Coffee, especially green coffee extracts, supply chlorogenic acid, which inhibits the glucose-6-phosphatase enzyme.16,17 Chlorogenic acid also inhibits glucose absorption from the intestinal tract and thus reduces after meal blood glucose spikes.

    Ketogenesis requires that the body preferentially use fatty acids for fuel. This cannot happen if either gluconeogenesis or glycogenolysis is not under proper control.

    L-Carnitine and Astaxanthin
    L-carnitine is a nutrient that, among other things, helps to shuttle fatty acids into the mitochondria for oxidation. In the discussion of HCA above it was noted that the combination of HCA and L-carnitine greatly improves the replenishment of glycogen stores after exercise. Unfortunately, tissue levels of L-carnitine are highly regulated and difficult to elevate to the extent necessary for ergogenic benefits in athletes. HCA improves L-carnitine metabolism by increasing uptake.HCA is an insulin memetic as well as an insulin sensitizer. HCA also shifts the body towards metabolizing fats, which makes L-carnitine's job easier. Another approach is to supplement with astaxanthin. Astaxanthin (≥4 mg/d) has been shown to reduce lactic acid accumulation during exercise, improve fatty acid oxidation and maintain better blood glucose levels while improving endurance. The mechanism may involve carnitine palmitoyltransferase I.18,19

    Conclusion
    Studies have demonstrated the importance of metabolic flexibility for maintaining cardiovascular health and reducing the risk of developing metabolic syndrome components. Likewise, studies have shown that the related ability to enter ketosis as needed for athletic purposes can render rich ergogenic rewards. Nevertheless, enabling ketogenesis or keto-adaptation, however desirable this might be, through dietary measures alone under modern circumstances in Western countries is not only inconvenient, but downright difficult. Fortunately, it is possible to enable keto-adaptation through the use of appropriate supplements. These include properly manufacture HCA salts, wild bitter melon extract, sesame lignans and green coffee bean extracts. L-carnitine and astaxanthin are two more supplements that fit into this schema.

    Endnotes
    1. Preuss HG, Mrvichin N, Clouatre D, et al. Importance of Fasting Blood Glucose in Screening/Tracking Overall Health. The Original Internist. 2016, March:13-15,17.18.
    2. Bjornholt JV, Erikssen G, Aaser E, et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care. 1999 Jan;22(1):45.9.
    3. Sears B. Anti-inflammatory Diets. J Am Coll Nutr. 2015;34 Suppl 1:14.21.
    4. Mauro DiPasquale, M.D., "Let the Fat be with You: The Ultimate High-Fat Diet," Muscle Magazine International (July and September 1992); "High Fat, High Protein, Low Carbohydrate Diet: Part I," Drugs in Sports 1, 4 (December 1992) 8.9.
    5. https://bengreenfieldfitness.com/2015/12/how-to-get-into-ketosis/
    6. Ishihara K, Oyaizu S, Onuki K, Lim K, Fushiki T. Chronic (-)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice. J Nutr. 2000 Dec;130(12):2990.5.
    7. Lim K, Ryu S, Suh H, Ishihara K, Fushiki T. (-)-Hydroxycitrate ingestion and endurance exercise performance. J Nutr Sci Vitaminol (Tokyo). 2005 Feb;51(1):1.7.
    8. Cheng IS, Huang SW, Lu HC, Wu CL, Chu YC, Lee SD, Huang CY, Kuo CH. Oral hydroxycitrate supplementation enhances glycogen synthesis in exercised human skeletal muscle. Br J Nutr. 2012 Apr;107(7):1048.55.
    9. Louter-van de Haar J, Wielinga PY, Scheurink AJ, Nieuwenhuizen AG. Comparison of the effects of three different (.)-hydroxycitric acid preparations on food intake in rats. Nutr Metab (Lond). 2005 Sep 13;2(1):23. See also notes 18 and 19.
    10. Clouatre, D., Talpur, N., Talpur, F., Echard, B., Preuss, H. Comparing metabolic and inflammatory parameters among rats consuming different forms of hydroxycitrate. Journal of the American College of Nutrition 2005;24:429 Abstract.
    11. Clouatre D, Preuss HG. Potassium Magnesium Hydroxycitrate at Physiologic Levels Influences Various Metabolic Parameters and Inflammation in Rats. Current Topics in Nutraceutical Research 2008;6(4): 201.10.
    12. Han N, Li L, Peng M, Ma H. (-)-Hydroxycitric Acid Nourishes Protein Synthesis via Altering Metabolic Directions of Amino Acids in Male Rats. Phytother Res.2016 May 4. doi: 10.1002/ptr.5630.
    13. http://www.totalhealthmagazine.com/Vitamins-and-Supplements/Going-WILD-with-Bitter-Melon-for-Blood-Sugar-Support.html
    14. Lim JS, Adachi Y, Takahashi Y, Ide T. Comparative analysis of sesame lignans (sesamin and sesamolin) in affecting hepatic fatty acid metabolism in rats. Br J Nutr. 2007 Jan;97(1):85.95.
    15. Ide T, Lim JS, Odbayar TO, Nakashima Y. Comparative study of sesame lignans (sesamin, episesamin and sesamolin) affecting gene expression profile and fatty acid oxidation in rat liver. J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):31.43.
    16. Henry-Vitrac C, Ibarra A, Roller M, Merillon JM, Vitrac X. Contribution of chlorogenic acids to the inhibition of human hepatic glucose-6-phosphatase activity in vitro by Svetol, a standardized decaffeinated green coffee extract. J Agric Food Chem. 2010 Apr 14;58(7):4141.4.
    17. Bassoli BK, Cassolla P, Borba-Murad GR, et al. Chlorogenic acid reduces the plasma glucose peak in the oral glucose tolerance test: effects on hepatic glucose release and glycaemia. Cell Biochem Funct. 2008 Apr;26(3):320.8.
    18. Malmsten C, Lignell A. Dietary Supplementation with Astaxanthin-Rich Algal Meal Improves Strength Endurance; A Double Blind Placebo Controlled Study on Male Students. Carotenoid Science. 2008;13:20.22.
    19. Aoi W, Naito Y, Takanami Y, Ishii T, Kawai Y, Akagiri S, Kato Y, Osawa T, Yoshikawa T. Astaxanthin improves muscle lipid metabolism in exercise via inhibitory effect of oxidative CPT I modification. Biochem Biophys Res Commun. 2008 Feb 22;366(4):892.7.