Supplements Target Ketogenesis and Metabolic Flexibility

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.

astaxanthin Ketogenesis Metabolic Flexibility Ketosis Ketogenic Diets Wild Bitter Melon Extract Green Coffee Bean Extract L-Carnitine