We all have been to restaurants where you sit down and they throw down a basket of bread before they take your order. Sometimes the bread is mediocre. Sometimes it’s brownish dense stuff and filled with nuts, berries, and twigs. And sometimes it’s hard to resist piping hot rolls with butter on the side. Whichever variety of bread it is they put before you though you must resist – if your goal is to be healthy and lean.
It is not the bread per se that is the problem so much here – it’s when you eat the bread. Your body sees bread as essentially sugar. The starches in the bread are broken down very fast in your digestive system (it even starts in your mouth). On an empty stomach this means you will absorb this sugar very quickly, which leads to a spike in blood sugar and a spike in insulin.
The significance of this was recently illustrated in a scientific study published in the Journal Diabetes Care. The researchers took a group of 11 individuals with Type 2 diabetes and had them consume a controlled meal on two separate days a week apart. The meal was the same both times but the order in which the constituents of the meal were eaten was altered.
In the first meal, the group started off by eating high glycemic carbohydrates (bread and orange juice) followed after 15 minutes by chicken breast and vegetables. A week later the order was reversed – the chicken and veggies were consumed first followed by the carbs. Both times blood glucose and insulin were monitored (before the meal and at various intervals during and after the meal).
What they found was the average glucose levels were reduced by 28.6% at 30 minutes, 36.7% at 60 minutes, and 16.8% at 120 minutes after starting the meal with chicken and veggies compared with the bread and OJ. The overall “area under the curve” for glucose during the time period was 73% lower. Levels of insulin after the meal (60 minutes and 120 minutes) were also substantially lower.
This study was done in type 2 diabetics but the phenomenon I expect would apply to everyone. Lower glucose levels and lower insulin levels should lead to greater appetite control, less fat deposition, a less pro-atherogenic environment, and possibly greater insulin sensitivity.
So skip the bread or save it for during or after the meal. It’s not hard, just do as Arnold was reported to have done in Pumping Iron and tell the hippie waitress that you don’t vont the bread because it’s not on your special sex diet.
Ghrelin is a 28 amino acid long peptide that is secreted in the stomach and released into the bloodstream. It is often referred to as the “hunger hormone”. Ghrelin is known to act directly on Ghrelin receptors in the stomach to increase gastric motility and gastric acid secretion. Gastric derived Ghrelin is also known to cross the blood barrier where it activates Ghrelin receptors in parts of the hypothalamus. In short, the activation of these Ghrelin receptors results in increases in activity of certain neuronal systems involved in appetite and energy homeostasis. Activation of hypothalamic Ghrelin receptors also stimulates the release of growth hormone from the pituitary gland in a significant and reproducible manner.
These anabolic and appetite stimulating properties have made Ghrelin a compound of much interest in the medical community – in particular for the management of cachexia. Cachexia is a condition that involves loss of appetite and lean body mass. It is a consequence of diseases such as cancer and AIDS and it often leads to rapid physical deterioration and eventual death.
Even before scientists discovered Ghrelin itself, they knew that its receptor existed and several synthetic Ghrelin analogs had already been developed. Several of these were small peptide molecules such as GHRP-2 and Hexarelin, but orally active non peptidyl Gherlin analogs such as Ibutamoren (MK-677) were also developed and tested. All of these compounds shared the classical effects seen with natural Ghrelin – namely increases in appetite and elevations in circulating GH and IGF-1.
Today there are dozens of Ghrelin analogs in the drug development pipeline but none have yet achieved FDA approval and made it to market. Many of these however are being sold through “research chemical” websites to athletes (though such sales are legally questionable at a minimum). Most of these need to be injected although at least one (Ibutamoren) works orally.
Remarkably, there appears to be an actual natural herbal medicine from Japan that has the same end results as the synthetic Ghrelin analogs. This concoction is known as Rikkunshito, and it consists of a mixture of extractions from eight different herbal constituents.
Rikkunshito is classified in Japan as a “Kampo” medicine. Kampo medicines are traditional herbal medicines which have been approved for medicinal use by the Japanese Ministry of Health and Welfare.
The traditional use of Rikkunshito has been to treat indigestion / heartburn, as well as stimulate the appetite. Recent research has shown that Rikkunshito regulates the secretion, receptor sensitization (in hypothalamus), and degradation of Ghrelin. Numerous studies (several on actual humans) have demonstrated this effect and shown it to be effective in increasing appetite, gastric motility, and body weight in patients suffering from cachexia / anorexia syndrome.
Two chemical constituents of Rikkunshito proposed to be responsible for these effects are Hesperidin and Atractylodin. Hesperidin is thought to increase Ghrelin secretion via antagonizing a subtype serotonin receptor known as the 5-HT2b/2c receptor. Atractylodin is believed to sensitize the ghrelin receptor, thereby amplifying the physiological effects of the increased ghrelin secreted into the bloodstream.
The literature on this herbal medicine is quite impressive in regards to its effects on Ghrelin activity and its effects on reversing cachexia (improving appetite and digestion, as well as improving body weight). I haven’t found any literature directly documenting its effect on growth hormone / IGF-1, however one would expect it to have that property as it works by potentiating Gherlin secretion and signaling.
Taurine is an organic acid found in the body that is involved in a variety of processes. It has been studied for heart failure, high cholesterol and blood pressure, fatty liver and multiple other conditions. One of the more interesting effects its ability to enhance testosterone levels and testicular function. In adult and aged rats taurine increased testosterone levels, while also increasing luteinizing hormone, nitric oxide and sexual response. Other studies show taurine provide general testicular protection from a variety of toxins like heavy metals, cancer treating drugs, and nicotine by virtue of its an antioxidant effects.
A new study shows some interesting benefits of taurine that could be specific to the user of anabolics. Rats were given nandrolone decanoate (deca) alone, or nandrolone with taurine for 8 weeks (and placebo only, and taurine only). The result was that taurine reversed several significant nandrolone induced side effects. The most important being that it normalized testosterone levels while taking nandrolone. In addition it prevented changes in sperm characteristics and in key steroid forming enzymes.
The idea of endogenous testosterone being “shut down” while on anabolics is well known, and there have been a plethora of strategies for preventing or reversing this. Usually these strategies are based on some intervention in the negative feedback loop caused by excess steroid signaling the stopping of LH production in the pituitary. This study brings to light a new idea that I haven’t seen discussed much in regards to keeping endogenous testosterone production intact while using exogenous hormones. This idea is that the decrease in T level is from oxidative damage resulting in apoptosis in the leydig cells.
So while gonadotropins are important in the production of testosterone, perhaps looking into testiculo-protective supplements could be an alternate strategy to keep endogenous T production functional, at least in the short term.
Adv Exp Med Biol. 2013;776:347-55. doi: 10.1007/978-1-4614-6093-0_32.
J Biomed Sci. 2010 Aug 24;17 Suppl 1:S9. doi: 10.1186/1423-0127-17-S1-S9.
Toxicol Appl Pharmacol. 2015 Feb 1;282(3):285-96. doi: 10.1016/j.taap.2014.12.007. Epub 2014 Dec 24.
Editors Note: The following article is a guest blog by Farmacist
When ketogenic diets came back in vogue in the 90’s, bodybuilders were looking for ways to speed up getting into ketosis. The diets were cyclic and it took several unpleasant days to get into full blown ketosis. Glucose disposal agents were typically used, but some of the more daring folks used low doses of insulin to speed the process. The idea was, the faster you get into ketosis, the more fat burning days you would get per cycle. This of course carried the risk of overdosing and becoming hypoglycemic, so this was probably not done by too many people.
Today something like Ketoforce could get your ketones raised quickly, to avoid the unpleasant shift from glucose to ketones for fuel by your brain. That said there are some interesting things that could be, in theory, done with insulin and ketosis.
Disclaimer: Insulin can kill you, do not use insulin without medical supervision. This is not a how-to guide, merely some thoughts on possible pharmacological processes.
The prospect of using insulin without carbs could be a way to reap some of the anabolic benefits of the hormone with a lower likelihood of fat gain, or it could be a way to speed “full” ketosis or ketoadaption by driving glucose levels down.
Something that may not be well known is that ketones are protective of the brain during hypoglycemia. In fact there are studies that show injecting insulin into someone with high levels of ketones will bring blood sugar into dangerously low levels, without the patient exhibiting hypoglycemic symptoms.
See this summary: http://caloriesproper.com/40-years-ago-a-group-of-researchers-turned-ketosis-into-poetry/
Insulin is known to decrease hepatic ketogenesis, so slowing ketone production may be an issue if using exogenous insulin. There is some animal data showing that ketone production from octanoate is preserved however, when insulin is administered. This is potentially important as medium chain triglycerides are about 70% octanoate.
Do humans continue to make ketones from octanoate when insulin is given? Are exogenous ketones enough to combat low blood sugar? Do you need to be ketoadapted to be protected?
While it would make interesting research, the unknowns still make this a dangerous proposition.
Oxytocin is a relatively small peptide hormone (nine amino acids) that is produced in the posterior pituitary gland. Although it is produced in both men and women, the most well known function of oxytocin is in females where it acts as a facilitator of uterine contractions during labor, and as a stimulator of milk release from the breasts in the post-partum period. More recent research has implicated oxytocin in the emotional bonding response that occurs between females and their infant offspring, and also that which occurs with adult romantic partners over time. You may have heard that oxytocin is released after sex especially in women (which may be why women tend to be more affectionate afterwards). Oxytocin is also FDA approved as a drug to facilitate labor in women and to help with post childbirth bleeding.
Like many hormones in the body, science is discovering that oxytocin may have a wide variety of actions on multiple tissues – activities beyond the classical ones for which it is most well known. Most recently evidence has popped up suggesting that oxytocin is a factor in the regeneration of muscle tissue and that its levels are suppressed with age.
Researchers at UC Berkeley published a paper demonstrating that oxytocin is an indispensable factor in the healthy repair and maintenance of skeletal muscle tissue. They used young and old mice and showed that levels of oxytocin in the older mice were much lower than the younger mice. Administration of oxytocin (by subcutaneous injection) for a few days restored the ability of muscle to repair itself in these older mice to levels seen in younger mice. Conversely, mice bred with inability to produce oxytocin were born normal but quickly developed sarcopenia (muscle loss associated with aging).
The mechanism of this enhanced muscle regenerative capacity is thought to be due to increasing the proliferation and activation of muscle satellite cells. Muscle satellite cells are known to decrease with aging and they serve a key role in muscle recovery and growth. Injury (exercise induced or via trauma) causes the release of certain chemical signals which stimulate satellite cells to fuse with their parent muscle cells where they add myonuclei (the powerhouse of protein synthesis within the muscle cell).
It has been shown previously that muscle cells possess functional oxytocin receptors and that muscles themselves can manufacture oxytocin. One study in particular showed that in cattle the expression of oxytocin in muscle is increased dramatically in cattle receiving the anabolic steroid implant Revalor H, and it is speculated that oxytocin may be related to the increased muscle mass that results. The UC Berkeley study now shows that direct systemic administration of oxytocin may have positive effects upon skeletal muscle as well.
As I mentioned previously, oxytocin is an FDA approved drug so its safety profile has been examined. However its intended use is short term, and any usage to treat a condition such as sarcopenia would require more long term administration. Oxytocin is also available freely from veterinary stores and is actually not very expensive. I don’t really know what dosages might theoretically work in a human (if any dose would work at all).
Editors Note: The following article is a guest blog by Farmacist
Bioidentical hormone replacement is a popular treatment for women (and men) that uses steroids identical in structure to what the body naturally produces, instead of a nonhuman estrogen or progestin. In a certain percentage of patients, increased doses are needed to achieve a reduction in symptoms. There are patients who do not respond to increased doses, and some of these fall into a category of hormone hyperexcretors.
In these patients, a 24 urine analysis reveals metabolite level 50% to 1800% higher than what would normally be expected. For whatever reason, these patients ability to eliminate estrogen is upregulated, and they end up peeing out estrogen at too high of a rate to get the beneficial effects.
This is all great but as this blog isn’t targeted to postmenopausal women, what the significance of this?
Its very possible something similar happens with high levels of androgens. Historically, switching esters or mixing up the types of steroids used were strategies to avoid plateauing. A lot of talk about receptor sensitivity and up/down regulation has been discussed on this topic, but increased metabolism and elimination is an angle that hasn’t been covered as much. This certainly could be a factor in why response to an androgen decreases over time.
In the BHRT women, there is a strategy of using cobalt to affect steroid metabolism to essentially retain more drug in the body so it is able to stay active longer. The way this is accomplished to by taking small amounts of cobalt orally for a period of about 3 months.
There is mention of this being used in male BHRT as well and a few anecdotal experiences can be found on the web, but its far from certain that this would work. What is known is that oral cobalt can decrease the activity cytochrome p450 enzymes in the liver, and this can affect the metabolism of steroids.
Dose appears to very important in getting the desired effect from cobalt, as it may have opposing action at high doses as it does at lower doses.1 The BHRT women used in the neighborhood of 500mcg per day to restore hormone action, and this dose in humans is not expected to cause toxicity.1
In rats high doses suppress androgens and can cause testicular necrosis.2 Low doses of a cobalt compound has shown to improve the protein to fat ratio without affecting testosterone levels.3
3. US patent 4997828
Researchers at the University of South Florida recently had some very exciting research published in the International Journal of Cancer. http://www.ncbi.nlm.nih.gov/pubmed/24615175 The research team was led by Dr. Dominic D’agostino, and the goal of the study was to examine the impact of supplemental ketones and ketone precursors on metastatic cancer in mice. The research has important implications on the treatment of cancer and also possibly on the prevention of cancer.
Ketogenic Diet, Caloric Restiction, and Cancer
Recent research has strongly suggested that the ketogenic diet may prevent the spread of metastatic cancer (metastatic cancer is cancer that can spread from the original tumor site to other parts of the body). This research was pioneered by Dr. Thomas Seyfried from Boston College. Dr. Seyfried has used the ketogenic diet in conjunction with caloric restriction to successfully restrict metastasis, and in some cases actually shrink the size of tumors.
The concept is relatively simple. Cancer cells can generally only use glucose to energize their growth, while normal cells have the metabolic flexibility to use fatty acids and ketones in addition to glucose. So by starving tumors of glucose via calorie and/or carbohydrate restriction – while simultaneously providing abundant alternative fuels for the body and brain (the ketogenic diet) – you may halt the cancer without side effects.
The concept may be quite bold, but it is not new. A Nobel Prize physicist named Otto Warburg first conceived of the general idea back in the 1920s. Unfortunately, after the discovery of the structure and function of DNA in 1953, the popular view of cancer was that it was a disease of purely genetic origin. As a consequence, Warburg’s hypotheses were largely discarded. Hopes were high that a cure for cancer was just around the corner back then, but as we all know that was not to be. Luckily, within the last few decades some researchers have taken a second look at Warburg’s work and the “metabolic theory of cancer”.*
Using this “metabolic theory of cancer” as an inspiration, studies were undertaken examining the efficacy of caloric restriction and/or ketogenic diet in cancer survival. It was found that often the growth and spread of tumors was halted, and in some case actually reversed. These findings have garnered attention and have sparked some controversy. There are concerns with the practical applications of these dietary interventions in the patient population. One concern involves the idea of initiating caloric restriction while the threat of cachexia looms. Cachexia is the condition of lean tissue wasting that often occurs as a consequence of cancer, and it is cachexia which often kills the patient rather than the tumors themselves. Could caloric restriction exacerbate cachexia in some instances and lead to an earlier demise? In addition to the cachexia issue, how readily will patients be willing to endure the restrictive and often unappetizing aspects of the ketogenic diet?
What Dr. D’agostino and his team set out to find is whether or not metastatic cancer could be controlled via exogenous supplementation alone. He designed an experiment in which three groups of mice were inoculated with a highly metatstatic line of cancer cells that contained a luminescent tag (to enable clear imaging of the tumors). All the mice were given unrestricted access to a standard diet (60% carbohydrates). One group would have the diet alone while the other two groups would receive one of two different forms of exogenous ketone compounds in addition to the diet. The two exogenous ketone supplements used were 1,3-butanediol (BD) and RS-butanediol diacetoacetate (ketone ester or KE). Their metabolic conversions to ketone bodies is exemplified in the following diagram
The results of this experiment were remarkable. Despite being on a high carb unrestricted diet the groups taking the exogenous ketones exhibited dramatically less tumor infiltration throughout the body compared to the diet alone mice (as seen by bioluminescent imaging). Survival in the BD supplemented and KE groups were prolonged 51% and 69% respectively compared to controls as well.
These results seem to contradict much of what was assumed regarding how the ketogenic diet fights cancer. It has traditionally been thought glucose deprivation was necessary to starve the cancer. However in this study the mice were eating unrestricted amounts of a high carb diet, so glucose remained high. What could be going on here? The researchers speculate that the ketones themselves may be directly toxic to the tumor cells, via mechanisms such as disruption of energy production by glycolysis in the tumors.
This paper certainly will cause an upheaval amongst those studying dietary interventions for cancer. Now the possibility has been opened up for simple supplementation as a course of treatment using the synthetic ketone precursors used in the study, or perhaps even by using natural ketone supplements such as beta-hydroxybutyrate (BHB) salts. Supplementation would be a much simpler, convenient, and patient compliant alternative to the more drastic dietary interventions previously thought necessary.
*The metabolic theory of cancer postulates that cancer does not arise because of damage to our DNA resulting in mutated oncogenes, but rather it arises as a result to disruptions in processes of energy production in our mitochondria. The disruption of oxidative phosphorylation in the mitochondria forces a cell to rely on the less efficient glucose driven anaerobic glycolysis. It is this dysfunction in energy production which then is thought to turn on existing oncogenes in the nucleus, causing the cell to turn cancerous.
Anabolic drugs are not dead, in fact research to develop new ones are aggressively being pursued to address medical situations such as cancer cachexia (wasting secondary to cancer) and sarcopenia (age related loss of muscle mass). Both of these categories are potentially huge money makers. Amongst the weird drugs that are being proposed for these applications is one that kind of boggles my mind. It is actually a current drug used to treat high blood pressure. Well, I guess you can say HALF of the drug is being developed as an anabolic
The drug I am referring to is called Pindolol, and the “half” that is being developed is S-pindolol. What I mean by that is that Pindolol is what is known as a racemic compound (it exists in a 50/50 ratio of right and left handed isomers) and the drug proposed as an anabolic is S-pindolol (the left handed isomer only). Many drugs are like this and often only one isomer is the active one. Take for example methamphetamine. Its active isomer is the right handed one. The left handed one is weak enough that it is allowed to be sold over the counter as a component of vicks inhalers.
Pindolol is sold to treat high blood pressure and it does so by blocking the effects of adrenaline like compounds on the heart (it’s a beta1 blocker). As such it decreases the force and frequency of heartbeats and thusly blood pressure decreases. Interestingly, pindolol also has agonist effects upon receptors of adrenaline like compounds too, specifically on skeletal muscle (it’s a beta2 agonist). You may be familiar with beta2 agonists such as clenbuterol. They are anabolic
Anyway, this compound (the S-isomer of pindolol which is the isomer that does stuff) is poised to be marketed as an anabolic for cancer cachexia and maybe sarcopenia. Studies have been done that have demonstrated muscle growth in these models. Myostatin has been shown to be suppressed amongst other things, which are effects we know happens with beta2 agonists (at least in the short term). Cool thing is that unlike most beta2 agonists (clen) this has no stimulatory effect on the heart. Not so cool thing is that it actually has a depressive effect on the heart, which means your exercise performance can suffer because your heart won’t beat fast and hard enough to support your efforts (that is if you train like a man)
Anyway, interesting stuff I suppose and expect it to appear on your banned list soon
DMAA, also known as methylhexanamine or “geranamine” is a controversial stimulant ingredient used in weight loss and energy supplements. In April of this year the FDA made a strong statement regarding its health dangers and its lack of legal standing as a nutritional supplement. Companies selling DMAA products for the most part stopped selling the stuff, and those who didn’t fully comply were subject to harsh enforcement actions by the FDA.
It took a long time for the FDA to act on DMAA, and that was in large part due to the fact that they really didn’t have clear cut evidence that the product was dangerous. Outcries by certain people that claimed the product was responsible for various adverse medical events and deaths however became louder and louder. These claims were not substantiated by any medical evidence though and so were not enough for the FDA to act upon.
The most publicized adverse health events regarding DMAA involved the US military. The deaths of four servicemen were being blamed on DMAA. As a consequence, the department of defense commissioned a safety study on the compound to determine whether it indeed was dangerous and to blame for the soldiers’ deaths (as well as other medical incidents involving soldiers). This was to be the study that the FDA could rest its hat on and justify an emergency action against DMAA.
Things started getting strange though. The study was supposed to be finished in February 2012. That date came and went and no word on the study results were announced. Then word came that the study was taking longer than expected and would be done in December 2012. Well December 2012 came around and still no word. Months passed and no one seemed to be talking about the huge DOD study that was supposed to prove once and for all that DMAA was deadly.
Then in April 2013 the FDA announced that it considered DMAA illegal to sell and warned of a whole variety of potential health risks. No mention of the DOD study which was supposed to provide the scientific validation was made – the FDA announcement was based simply on theory.
What happened to the DOD study? Well, in August the results were finally released (four months after the FDA’s arbitrary action). They were released with such lack of fanfare and media coverage that even I was not aware of the results until just today (almost two months later). Essentially they found that despite a high apparent usage of DMAA by soldiers (as much as 15 percent) the substance at doses recommended by manufacture poses a low risk of serious harm for most service members. The study basically exonerated DMAA from being responsible for the deaths of the four soldiers. They cautioned though that the “potential” of DMAA to cause harm still exists and ongoing studies would be needed to fully understand the health issues (I guess two years wasn’t enough).
Anyway, I have my own take on this situation. I think it was clear quite a while ago that the DOD study was not going to provide the smoking gun that was expected and hoped for. At that point the results were kept hush hush and the FDA decided to act anyway against DMAA. Then they waited four months to quietly announce the study results – so quietly that it took me six weeks to even be aware of them.
On my last blog I promised I would show you some data on my KetoForce product (BHB mixed salts). I have two sets of data – the first showing blood beta-hydroxybutyrate (BHB) responses and the second showing specific changes in physiological parameters during a controlled exercise experiment.
The blood data was done at a university on a set of subjects and the average changes in BHB levels are what this graph shows
These subjects drank a diluted version of the KetoForce product that was essentially equivalent to 36mL of KetoForce.* The product was consumed on an empty stomach and as you can see blood BHB levels rose pretty quickly. Levels appear to stay decently elevated until round the 180 minute (3 hour) mark. 30-60 minutes seems to be the sweet spot for maximum blood levels, so for pre-exercise use one should probably time the ingestion accordingly.
The exercise data I have was done using a 20% solution of the BHB salts which was equivalent to 40 mL of the KetoForce product. The data was done by an independent individual that does such research for a non-profit organization. Out of respect for this fact – and the fact that the data is only preliminary (more research is going to be performed) – I won’t report the full data here. I will give a glimpse into the most interesting thing he found though.
First of all this individual was ketoadapted. Ketoadapated means he had been on a ketogenic diet for a period of time long enough so that he was in full ketosis and had developed a good ability to utilize ketones. He did a bike exercise that was set up so the workload was maintained at a constant level roughly equal to 60% of his VO2 max. During the first stage he did the exercise for twenty minutes without the salts, and during the second stage he consumed the salts 60 minutes prior to the exercise bout.
One of the things that was measured was the amount of oxygen consumed during the exercise bouts. Theoretically, ketones should reduce oxygen consumption because they are known to generate more cellular energy per unit oxygen burned compared to glucose and other energy sources. The data he got with the BHB salts strongly suggested that this theory was at work during the experiment. Below is the difference in oxygen consumption reported as a percentage between a bout without the salts and a bout with the salts.
Last 5 minutes – minus 8.8%
Last 10 minutes – minus 7.7%
Last 15 minutes – minus 6.6%
Apparently there was a substantial decrease in the amount of oxygen he needed to maintain the workload after taking the salts. Very interestingly, this decrease in oxygen demand got more prominent as the session went on as well.
BHB salts are natural products that mimic the nutritional state of ketosis and have been studied in the past for medical applications as well. KetoForce is the first introduction of these salts to supplement and fitness industry so we are very early on in regards to figuring out how best to use them. This preliminary data does give us some clues on how they may be used (timing wise) and what benefits they may offer. We are very hopeful that our collaborations will enable us to generate a lot more research on the product (such as what performance benefits might be seen in non ketoadapted people) in the very near future.
* The KetoForce label suggests a serving size of 30mL instead of 36mL. Since I don’t expect all my customers to own graduated cylinders many will have to use the cap for measuring, and the cap holds 10mL . For this reason I rounded the serving size off to 30mL.