macronutrients

Beyond Calories In and Calories Out

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Since the early 20th century, calories have been equated to health and energy. The assumption is that calories, no matter their composition, equal energy, and energy equals health. Strictly speaking, this is correct. The body will take whatever it is given, and to the best of its ability, convert it into cellular energy or adenosine triphosphate (ATP). That process produces heat and heat is the unit of change underlying the concept of calories. Mathematically, a calorie or kilocalorie (kcal), the unit used in food science, represents the heat or energy required to raise the temperature of 1 kilogram (kg) of pure water to 1° Celsius. This equation is used to calculate the heat content of food and determine the amount of heat energy produced as the food passes through the body. Another simple metric called the basal metabolic (BMR) is used to calculate the energy one requires to survive. From these two metrics, we get the calories in/calories out framework that dominates conversations about health and disease.

According to this framework, if the two numbers balance, we should have sufficient energy to meet the demands of daily living. If we consume more calories than we burn then, we should have excess energy, which can be used to increase one’s activity level or be stored as potential energy for use in the future. In today’s sedentary environment, it is usually the latter. Conversely, if we consume fewer calories than necessary, decrements in energy and weight loss should follow. In either case, energy is simply a matter of physics. Heat energy is transferred from one source – the food, to another – the body, or from the body to the environment at large, as one uses the energy in daily living and it dissipates.

This is the framework that has guided the medical profession, the food industry, and countless weight loss gurus for generations. To that end, it is of little to no concern what these calories are comprised of and very little thought is given to the endogenous processes underlying the generation of heat or energy. This framework allows us to represent health and illness mathematically. It is simple, recognizable, and easily understood, and perhaps that is why we hold dearly to it but is it accurate? What if there is more to this story? What if energy is not just a matter of heat transfer and what if the content of the calorie matters as much or more than the calorie itself? To answer that question, we need to determine what type of energy the body needs to survive and how that energy is derived.

What is Energy?

If energy is not a matter of calories, at least not in the sense that is portrayed, what is it then? In the body, energy comes in the form of ATP molecules, produced primarily by the mitochondria. In broad terms, ATP is the result of a series of reactions that combine oxygen with components of metabolized foods. Part of this process takes place in the cell but most of it takes place in the cell’s power plants, the mitochondria.

If all is going well, derivatives of fat, protein, and carbohydrates, the macronutrients contained in food, are shuttled into the mitochondria, through what is called the tricarboxylic acid (TCA) cycle (also called the Krebs or citric acid cycles), combined with oxygen, and through a series of reactions, collectively called oxidative phosphorylation (OXPHOS), produce ATP. From the oxidation of one glucose molecule, we get around ~30-36 ATP molecules. From one fatty acid molecule, we get over 100 ATP molecules, and from the amino acids, we get either substrates for the synthesis of other proteins, more glucose to metabolize and feed into the mitochondria (amino acids can be converted into glucose via gluconeogenesis), or another compound called pyruvate that may also be used by the mitochondria to make fuel or converted into lactate.

When things are not going as well or when quick energy is needed for certain functions, a number of extra-mitochondrial pathways, are used to break down the various macronutrient components to provide energy. There are two key pathways here. One is called glycolysis and the other is called the pentose phosphate pathway (PPP), which connects glycolysis with the TCA and OXPHOS and performs a few other important tasks like providing substrates for DNA and RNA synthesis. The PPP nets 1 ATP molecule per molecule of glucose, while glycolysis nets about 2 ATP molecules per molecule of glucose. A third pathway, used primarily in quickly replicating immune cells and cancer cells, involves shuttling glutamine, an amino acid, through the side door of the mitochondria to produce ~24 units of ATP per unit of glutamine. Severely stressed neurons use this pathway as well.

Which pathway is used to produce ATP may alternate according to to need, cell type, fuel type, micronutrient, and/or oxygen availability. Some cells metabolize a good portion of their energy in the cytosol using glycolysis while others rely almost exclusively on the OXPHOS in the mitochondria. This flexibility allows cells to adapt rapidly to changing circumstances. If one macronutrient is not available, energy is derived from another. When a micronutrient (vitamin or mineral) is not available, the products are diverted through other pathways, and when there is limited oxygen, glycolytic pathways will take over. All of this is meant to help the body metabolize different compounds and maintain energy homeostasis relative to environmental demands.

Different Energy Pathways for Different Cells

The body requires an enormous amount of energy to meet the demands of life. We effectively turn over our weight in ATP every single day. Every. Single. Day. That is absolutely remarkable. When we exercise, we produce even more – 0.5 to 1.0 kg per minute. Fully 95% of this energy comes from mitochondria, making mitochondrial fitness of the utmost importance. Many cells contain anywhere from 1000 to 2500 mitochondria and can represent from 25% to upwards of 60% of the cell volume. Accordingly, the average cell may use upwards of 10 billion units of ATP per day.

The production of ATP is critically important for survival and so its manufacturing of ATP is inherently dynamic and adaptable. The body will take whatever it is fed and turn it into energy using whichever pathway is available. So even when we feed ourselves garbage food, the body will do its best to manufacture some quantity of energy. The body does, however, have preferences. Importantly, different types of cells favor specific fuel types or pathways.

Skeletal muscles, for example, use fatty acids shuttled through the mitochondria for fuel when at rest but switch over to glucose, creatine, or lactate via glycolysis as exercise intensity and/or duration increase. Creatine, synthesized in the liver from glycine (and taken as a popular supplement in the athletic community), is part of a system that effectively recycles ATP in skeletal muscle during intense bouts of exercise. Lactate, originally believed to be a waste product, is actually an important fuel source. The ability to repurpose lactate, and metabolize it into ATP, whether via glycolytic pathways or via derivatives that will enter the mitochondria, is a major determining factor in forestalling fatigue for athletes and non-athletes alike.

You might be thinking, if glycolysis produces less energy per unit of glucose, why would the body choose to use it? Two reasons. The first is speed. Sometimes the energy is needed more quickly than can be provided by the mitochondria. So the body trades some capacity for speed. This occurs in fast-growing cells like the immune cells that need to replicate quickly during an infection. Similarly, high-energy situations like intense and quick bouts of exertion favor glycolysis. These are normal and adaptive. Secondly, glycolysis and its sister pathway, the PPP, also provide important components for cell building. If that is what is required, those are the pathways that will be used.

Unfortunately, glycolysis is also favored when the mitochondria are struggling. Here, molecules that would normally be shuttled into the mitochondria are diverted into other paths, and energy production is diminished. This is common in patients with metabolic disorders. The excess intake of sugars often paired with a lack of micronutrients overwhelms mitochondrial capacity, and as a result, much of the glucose remains in the cell and is either metabolized into what few ATP the cell can muster via glycolysis or shuttled towards other pathways that will act as waste management and expend rather than create energy. Cancer follows this pattern.

The continuously active heart cells require a huge amount of energy, approximately 6 kg of ATP per day to pump blood, most of which comes from the mitochondria. At rest, ~90% of the heart’s ATP comes from the oxidation of fatty acids in the mitochondria. During exertion, there is a slight shift in substrate preference and more glucose is used. Instead of a 90/10 split of fats to glucose, with activity, the split is closer to 60/40. In either case, these numbers show us that mitochondrial capacity and diet are incredibly important for heart health. Low fat, high carbohydrate diets, as have been recommended for decades, go against the fuel preference of a healthy heart. The result of this type of diet is evident in the cardiovascular disease associated with metabolic syndrome. With metabolic syndrome, which represents nothing more than dietary damage accrued over time, the mitochondria lose the capacity to metabolize fatty acids for ATP and instead must rely exclusively on glucose for energy. The resulting decrements in energy underlie many of the aberrant patterns in rate, rhythm, and pressure. The heart simply does not have the energy to pump effectively at rest but especially under stress. Importantly, with metabolic syndrome, dysfunction expands beyond the heart, and other cells will also lose the capacity to metabolize fatty acids, gradually shifting to a more glucose/glycolysis dominant metabolism.

The brain consumes a substantial amount of glucose to meet energy needs (5.6mg of glucose per 100g of brain tissue per minute), with neurons using up to 80% of that energy. While the brain represents only about 2% of the body’s mass, it consumes 20% of the daily energy budget. Since the brain and the nervous system effectively manage all aspects of survival, decrements in energy metabolism have deleterious effects not only on the range of behaviors typically attributed to the brain, thinking, memory, planning, speech, emotion, movement, and the like but also on the automatic or autonomic control of organ function. For example, the parts of the brain located in the back of the head, collectively called the autonomic system (the cerebellum and brainstem, together with the nerves that flow through the spinal cord to the various organs and tissues), are exquisitely sensitive to changes in energy availability. The brainstem especially, because it controls breathing and heart rate, the two most important functions for survival, requires massive quantities of ATP. When energy availability is compromised, heart rate, breathing, and other autonomically controlled systems become dysregulated leading to what is now called dysautonomia.

Although most of the brain’s energy is derived from the oxidative phosphorylation of glucose within the mitochondria, here too, lactate recycling, extra-mitochondrial pathways like the PPP and glycolysis also play a role. Additionally, as ketogenic diets have shown us, the brain may use ketones derived from fatty acids as a fuel source.

Even proteins may be used for brain fuel. This is a relatively new discovery and not widely appreciated, but a set of neurons in the hypothalamus called the orexin or hypocretin neurons (same neurons, different names), require amino acids to fire. Specifically, and in order of potency, glycine > aspartate > cysteine > alanine > serine > asparagine > proline > glutamine induce orexin firing. This is important because these neurons are the primary energy sensors in the brain. They are responsible for maintaining wakefulness, providing the motivation to eat, and monitoring brain energy levels as a whole. Mutations in these neurons are responsible for narcolepsy, but due to their energy-sensing role, any disruption in brain energy, may force sleep and induce anorexia. In other words, these neurons control survival functions that become disrupted when ill. Low concentrations of orexin/hypocretin lead to what is called ‘sickness behaviors’ – the behaviors that every organism exhibits when ill. These neurons are also involved in precipitating migraine implicating brain energy deficiency here too. Interestingly, unlike other neurons in the brain, where glucose spurs activity, in these neurons, glucose spurs inactivity, perhaps through associated inflammation. Glucose, particularly high glucose, will cause these neurons to stop firing, which may be perceived as excessive fatigue, an insatiable need for sleep, and when severe enough, coma.

Of interest, the most important amino acid for the proper activity of these neurons is glycine. Glycine is an essential amino required for protein synthesis and repair. It is also an excitatory neurotransmitter in its own right, affecting other neural systems. Glyphosate, the chemical used on virtually all commercially grown agriculture (and thus, consumed by all commercially grown livestock), is a glycine analog. That means that whenever we consume commercial foods where glyphosate-based herbicides are used liberally, we are substituting natural and endogenous glycine for a synthetic analog. This substitution has a long list of health-derailing effects. Another ill-effect to add to that list may be the inappropriate regulation and responsivity of the orexin/hypocretin neurons.

The Composition of Calories

The section above illustrates the necessity for providing a variety of whole and uncompromised foods to fuel the body and it should fundamentally shift how we perceive the energy capacity of different food types. The body requires a variety of fuel sources to function appropriately. From the calorie-focused perspective of energy, none of this matters. It is assumed that so long as there are ample calories, energy production will be maintained at sufficient levels. The makeup of those calories is inconsequential to ATP output. This is clearly incorrect. For even if we look only at the raw numbers of units of ATP per pathway, it is evident that the composition of the diet matters. Someone who eats a predominately carbohydrate-based diet will produce quantitatively fewer ATP molecules than someone whose diet derives the bulk of their calories from fats. Similarly, the ability to funnel macronutrient components through the mitochondria and to run OXPHOS will produce more energy than if one’s cells are stuck in the glycolytic pathways. When a diet is skewed towards one type of food, the pathways that rely on the other macronutrients will be impacted negatively and this, in turn, will affect the organs that prefer one type of fuel over another.

If we dig a little deeper and look at the composition of consumed carbohydrates and fats, there are even more differences to consider. For example, carbohydrates coming from refined sugars like high fructose corn syrup (HFCS) produce less ATP than those that come from whole and unadulterated grains, fruits, or vegetables. In fact, the metabolism of HFCS requires ATP rather than produces it, and as an added complication, a good portion of the metabolized products derived from HFCS never enter the mitochondria but are instead converted to triglycerides and stored as fat. Similarly, consumed fats that come from animal fats versus seed oils, differ in their ability to produce ATP. Soybean oil, an oil extracted from soybean seeds, not only incites inflammation and a host of other ailments, but it downregulates the enzyme that sits at the entry point to the mitochondria, effectively blocking glucose metabolism and shifting everything to glycolysis for a huge net loss in ATP production. Since all heavily processed foods contain both of these ingredients, consuming these products with any regularity diminishes, and likely damages mitochondrial function. The net result is poor energetic capacity.

And if we dig deeper still, we find that the thousands of chemicals used to grow, preserve, enhance, and package these products, leach nutrients, derail mitochondrial functioning, and in many instances, evoke mitochondrial cell death. Consuming these foods, as so many of us are inclined to do regularly (57% of kcal in the American diet is composed of ultra-processed foods), leads to poor mitochondrial function and limited energetic capacity. It is not just the processed foods that have become problematic though. Conventionally grown produce is less nutritious than what was grown a few decades ago before the adoption of glyphosate-based herbicides and the genetically modified plants designed to withstand these chemicals became so pervasive. As discussed previously, glyphosate-based herbicides like Roundup that are ubiquitous in conventional agriculture (1.8 billion pounds of glyphosate used annually, enough for 4 pounds per person per year), block glycine. These herbicides also chelate (remove) minerals from the soils and plants and from the humans who consume these products. Minerals like calcium, magnesium, zinc, and manganese, which, as we will see later, are critically important for mitochondrial function. Indeed, the original patents for glyphosate involved its industrial descaling capacity, exactly the mechanisms enacted in the human body. It should be noted though, that glyphosate is just one of the tens of thousands of chemical toxins we are exposed to daily, most of which have never been tested for safety but instead are assumed to be safe under the poor regulatory template called GRASgenerally recognized as safe.

Each toxin that we ingest (or breathe), requires an ATP-using response from the body, thus diminishing potential reserves by some quantity. One can imagine, how over time the repeated consumption of these types of products might fundamentally alter mitochondrial function and reduce ATP capacity. Importantly, since the gastrointestinal (GI) system provides the interface between consumed foods and the rest of the body and is responsible for the digestion, absorption, and metabolism of food-based nutrients and excretion of toxicants, reduced mitochondrial functioning e.g. reduced ATP in the GI system is doubly problematic. Not only is GI functioning disrupted and oftentimes damaged by these types of foods, but the ability to derive nutrition becomes impaired as well. It takes energy to make energy and it takes energy to extract and metabolize nutrients and excrete waste products. Commercial foods, while high in calories and non-caloric additives are low in energy. These foods lack actual nutrients and nutrients are what mitochondria need to make energy.

How Do We Fix This Mess

It should go without saying that we ought to eat better and avoid food and other toxins where we can, but the food landscape is such that this can be difficult, especially if one is already ill and reactive to many foods and/or other substances. In those cases, it is important to understand what it takes to make energy from food, determine what is potentially missing from your diet, and replenish accordingly. This is not easy and will take a fair amount of detective work on your part, but it is possible.

We briefly covered the macronutrients, here we will look into the micronutrients. Micronutrients are vitamins, minerals, and some metal ions. In generations past, before we sterilized the soils with chemicals and modified the plants to withstand those chemicals, one could consume a complement of these micronutrients so long as one had a reasonably balanced diet. It is here where the concept of calories made a little more sense when food was food and not some commercially derived concoction. That is no longer the case. The advent and escalation of herbicides, pesticides, and the slew of additives, preservatives and other noxious chemicals in the food chain have effectively stripped modern foods of nutritional capacity while retaining caloric content. This means, that for many people, supplements will be required. Which ones and what dosages, however, will vary significantly. For that reason, it is important to understand how the mitochondria work so that you may become your own expert.

Broadly, for foods to be metabolized into energy, for any macronutrients to enter the mitochondria and run OXPHOS, vitamins and minerals must be available to power the enzymes leading to and through the mitochondria. If there are insufficient vitamins and minerals both in general and relative to the concentration of macronutrients (high calorie, low nutrient foods) or demand (toxins, stressors, illness), the TCA cycle does not work, OXPHOS does not work well, the body has to shift to alternate pathways. With this shift, not only is ATP reduced but because these pathways burn dirtier, more endogenous pollutants, like reactive oxygen species (ROS), are released. The oxidative stress that ensues damages mitochondrial membranes, further taxing mitochondrial capacity. This damage simultaneously demands more energy to resolve while reducing the capacity to produce that energy. Over time, the ability to manufacture ATP becomes so disrupted and produces so much oxidative stress that the entire process of extracting and metabolizing foods into energy further damages the mitochondria. Eating the very nutrients the body needs becomes a stressor and the individual becomes stuck in a seemingly never-ending negative cycle of malnutrition causing more malnutrition with any attempts to rectify inducing negative reactions. This is the state I find many people with chronic illness in – in desperate need of nutrients but unable to consume them.

Let us look briefly at the micronutrients involved in deriving energy from proteins, carbohydrates, and fats. Below is a graphic from the book I co-authored with Dr. Derrick Lonsdale. While it focuses on thiamine, it lists many of the other nutrients required for mitochondrial metabolism. Notice that within each pathway, a variety of vitamins, minerals, and metal ions are necessary to power the multiple enzymatic reactions require to produce ATP. The B vitamins and magnesium, in particular, play an important role in the early phases of these processes.

Mitochondrial nutrients

If any of those micronutrients are missing or are in short supply, the enzymes requiring those nutrients will not work as efficiently and the capacity to produce ATP will decline. With that decline comes a slew of compensatory reactions that will reallocate resources based on energy availability. Those reactions frequently involve inflammation, altered hormone regulation, and other adaptive measures, as reduced energetic capacity is a signal to other mitochondria and other cells that something is wrong.

Nothing works without energy and energy is impossible without the vitamins and minerals that drive mitochondrial function. Not even respiration is possible. Cellular respiration, the most fundamental form of respiration, the activity that breathing itself, requires critical micronutrients. Oxygen cannot be used or trafficked appropriately creating a state of hypoxia. Hypoxia, I believe, is what drives most modern illnesses. So let us take a look.

Micronutrient Deficiency Driven Hypoxia: The Root of All Illness

Among the least well-recognized reactions to reduced nutrients is a type of hypoxia called molecular or pseudo-hypoxia. Here, unlike the typical obstructive hypoxia, nothing is blocking or preventing oxygen intake. What is missing are the micronutrients required to power key enzymes involved in oxygen utilization. Specifically, for cells to breathe and to utilize oxygen to produce energy, the mitochondria require adequate thiamine (vitamin B1), magnesium, and riboflavin (vitamin B2). Looking at Figure 1, you will notice that thiamine and its activating cofactor magnesium appear frequently throughout each of the pathways used to convert foods into energy. Indeed, they are what are called rate-limiting co-factors in these processes. Meaning that if their levels dip, everything else downregulates as well.

Importantly, thiamine, magnesium, and riboflavin, along with alpha-lipoic acid, are integral to the functioning of an enzyme complex called the pyruvate dehydrogenase complex (PDC). PDC sits atop the mitochondria and acts as a gatekeeper of sorts. With insufficient concentrations of these micronutrients, the metabolism of glucose into ATP is blocked. The metabolites of other macronutrients, after some processing also utilize the PDC as an entry point, and so they too will be blocked from entering the mitochondria. As a compensatory reaction, the mitochondria initiate a series of reactions that signal danger. Among them is the release of proteins called hypoxia-inducible factors or HIFs for short. Once released, HIFs then signal all of the other changes consistent with chronic illness like inflammation, hormone reregulation, altered immune responsivity, etc. These are meant to be short-term protective measures that reduce energy requirements and increase blood flow and oxygen to the cells. Unfortunately, because these are nutrient-driven reactions, they will not be resolved until the nutrients come back on board consistently. As a result, these patterns become entrenched, and therein lies the root of many chronic illnesses.

Symptomatically, early one and when this set of reactions is limited to specific tissues, injury and inflammation will appear regional to those tissues or organs.  The GI system, both because it sits at the interface between food consumption and nutrient absorption and because the microbes that inhabit the GI tract also require thiamine, will often show disruption first. The poor nutrient landscape not only impacts energetic capacity, disrupts peristalsis, and the movement of foods through the tract, but also shifts the microbial ecosystem towards more pathogenic microbes that adapt more easily to the nutrient-starved environment.

When nutrient deprivation goes on long enough and the HIFs become stabilized, not only do we see all of the compensatory reactions mentioned above, but when severe enough, we will see underlying molecular hypoxia manifest like a sensation that one cannot get enough oxygen, even though oximeter readings are perfectly normal. This is frequently referred to as air hunger.

Whatever the individual response, however, since mitochondria control life and death cycles at the cell level, ailing mitochondria that cannot manage these cascades effectively, die a messy, necrotic death that is highly inflammatory and immune reactive. What little intracellular ATP is available to power cell function is spit out of the cell and used as a danger signal to other cells. High levels of extracellular ATP are indicative of severe mitochondrial stress. When this happens, even less intracellular and intra-mitochondrial ATP is available to power basic survival functions, and importantly, to create more energy.

This begins the downward trajectory of chronic illness where one needs energy to make energy but simply does not have it; where one needs key nutrients to resolve the energy crisis but does not have the energy to metabolize those nutrients.

Resolution and Prevention

Ideally, we would prevent the downward trajectory of mitochondrial illness, but modern life, such as it is, presents innumerable threats to mitochondrial energetics. The biggest, of course, is poor diet. By focusing on the caloric content of foods, and the ease and speed at which we can prepare those foods, rather than their capacity to provide critical nutrients, we have missed the physiological purpose of eating – to provide energy to live and to function. In light of what is required to create energy from food, balanced macronutrients with an array of micronutrients, we must consider the composition of the foods we eat, especially when one is dealing with a chronic and seemingly treatment-refractory illness.

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This article was published originally on July 19, 2022. 

Thiamine Insufficiency Relative to Carbohydrate Consumption

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Thiamine (vitamin B1) is an essential micronutrient responsible for key reactions involved in the conversion of the foods we consume into the chemical energy substrate requisite for cellular function, adenosine triphosphate (ATP). Absent sufficient ATP, all sorts of metabolic functions become disordered leading to the disease processes that dominate western medicine. Chronic inflammation, altered immune function, hormone dysregulation, cognitive and mood disorders, and dysautonomias, all can be traced back to insufficient thiamine > inefficient mitochondrial function, reduced ATP, and the compensatory reactions that ensue.

Among the most common but least well-recognized contributors to thiamine deficiency is the regular consumption of a high carbohydrate/highly processed food diet. Although most of these foods are enriched or fortified with thiamine, perhaps staving off more severe deficiencies, the density of sugars overwhelms mitochondrial capacity to process these foods, both the thiamine and any other potential nutrients are excreted, while the carbohydrates themselves are stored as fat for future use. High-calorie malnutrition is a common contributor to thiamine deficiency in obesity but also may develop in presumed healthy athletes whose diets focus heavily on high carbohydrate intake.

Thiamine, along with other B vitamins is often deficient in vegetarian and vegan diets as well. Not only do fruits, vegetables, and carbohydrates contain minimal, if any, thiamine, but some have anti-thiamine factors and are high in what are called oxalates. Anti-thiamine factors found in some fruits and vegetables interfere with the absorption or digestion of thiamine. Oxalates are mineralized crystals of sorts that tend to build up and store in places like the kidneys (kidney stones), but also may store and cause problems anywhere in the body like bones, arteries, eyes, heart, and nerves. Effective oxalate metabolism and clearance requires thiamine. Since vegetarian and vegan diets are also carbohydrate intensive, thiamine deficiency and oxalate issues may be compounded. Thus, a number of common diets not only contain reduced thiamine content but cause an increased need for thiamine by at least three mechanisms; higher carbohydrate consumption overwhelming capacity, which is then magnified by poor carbohydrate and oxalate processing.

Add daily coffee, tea, and/or alcohol consumption to any diet, and whatever thiamine that is consumed is either inactivated by enzymes before being used or is unabsorbable. Add a medication or four and thiamine availability will tank simultaneously with an increased need. Medications both block nutrient uptake and/or increase the need for nutrients by inducing mitochondrial damage. Given that 70% percent of the US population takes at least one medication regularly, while 20% take four or more, it is safe to say, that a good percentage of the population is consuming insufficient thiamine to maintain mitochondrial function and health.

Are We Really Thiamine Deficient?

As an essential nutrient, thiamine must be consumed regularly to maintain sufficient concentrations. The question is how much thiamine is sufficient to maintain health? Current RDA values for daily thiamine intake suggest a little over a milligram per day is adequate for most adults. If this is true, then the minimum value can be attained through just about any diet including those dominant in highly processed, carbohydrate-dense foods, which are commonly either enriched or fortified with thiamine. Everything from bread to cereals and even junk food like Oreos have thiamine. Per the RDA values, none of us ought to be thiamine deficient and none of us ought to require thiamine supplementation, and yet, many of us are and do. Indeed, several studies, across disparate populations show that even by this minimum standard, deficiency is a serious health problem. From our book:

  • 76% of diabetics (type 1 and type 2)
  • 29% of obese patients, 49% of post-bariatric surgery
  • 40% of community-dwelling elderly, 48% of elderly patients in acute care
  • 55% of cancer patients
  • 20% ER patients (random sample, UK)
  • 33% of congestive heart failure patients
  • 38% of pregnant women, more with hyperemesis
  • 30% of psychiatric patients

It takes approximately 18 days to completely abolish endogenous thiamine stores in a diet that is completely devoid of thiamine. Except under total starvation, medical or industrial food production mishaps, and experimentally contrived situations, thiamine consumption is never completely abolished. It waxes and wanes by dietary choices and life stressors. According to rodent studies, it takes a reduction of greater than 80% of thiamine stores before the more severe neurological symptoms are recognizable. In humans, these symptoms include those associated with Wernicke’s encephalopathy, the various forms of beriberi, and dysautonomic function. These include but are not limited to: ataxia, changes in mental status, optic neuritis, ocular nerve abnormalities, diminished visual acuity, high-output cardiac failure with or without edema, high pulse pressure, polyneuropathy (sensorimotor), enteritis, esophagitis, gastroparesis, nausea and vomiting, constipation, hyper- or hypo-stomach acidity, sympathetic/parasympathetic imbalance, postural orthostatic tachycardia syndrome (POTS), cerebral salt wasting syndrome, vasomotor dysfunction, respiratory distress, reduced vital capacity, and/or low arterial O2, high venous O2.

With a less severe thiamine deficiency, symptoms are rarely recognized as such and often attributed to psychological manifestations. A not entirely ethical study done in 1942 involving 11 women on a low thiamine diet over a period of ~3-6.5 months found striking symptoms.

  • During this time all subjects showed definite changes in personality.
  • They became irritable, depressed, quarrelsome, and uncooperative.
  • Two threatened suicide. All became inefficient in their work, forgetful, and lost manual dexterity.
  • Their hands and feet frequently felt numb.
  • Headaches, backaches, sleeplessness, and sensitivity to noises were noted.
  • The subjects fatigued easily and were not able to vigorous exertion.
  • Constipation was the rule, but no impairment, of gastrointestinal motility, could be demonstrated fluoroscopically.
  • Anorexia, nausea, vomiting, and epigastric distress were frequently observed.
  • Low blood pressure and vasomotor instability were present in all patients.
  • At rest, pulse rates were low (55 to 60 per minute) but tachycardia followed moderate exertion. Sinus arrhythmia was marked.
  • Macrocytic, hypochromic anemia of moderate severity (3.0 to 3.5 million red cells) developed in 5 cases.
  • A decrease in serum protein concentration occurred in 8 subjects.
  • Basal metabolic rates were lowered by 10 to 33 points.
  • Fasting blood sugar was often abnormally high.

The study above demonstrated a rapid and dramatic onset of symptoms relative to a diet with limited thiamine. Depending upon caloric intake, the amount of thiamine allowed was approximately 1/3 to 1/5 of the amount recommended by the RDA. Admittedly, the RDA for thiamine is low, to begin with, but even so, this was not a complete absence of thiamine. Since the study took place in the early 1940s, it is difficult to ascertain the specifics of the diet. Nevertheless, it demonstrates a clear association between general health and one’s ability to function, and thiamine insufficiency.

High Carbohydrate Diets Equal Lower Thiamine

More recently, a short and very small study (12 days and 12 participants) of active young men and women (ages 25-30) investigated the relationship between carbohydrate intake and thiamine status. Thiamine was measured in blood, plasma, urine (creatinine), and feces at four time points: at baseline, before the study began, during an adaptation phase where carbohydrate intake represented 55% of the total caloric intake, and during the two subsequent intervention phases, where carbohydrate intake was increased to 65% and 75% of the total caloric intake, respectively. Both caloric and thiamine intake was held constant throughout the study despite the increased intake of carbohydrates. Activity levels were also held constant. Across this short-term study, as carbohydrate intake increased, plasma, and urinary thiamine decreased. Excretion through feces remained unchanged. Transketolase enzyme activity was also measured but remained unchanged. Given the short-term nature of this study, the fact that transketolase remained unchanged is unexpected. In addition to the decreasing thiamine values, there were several changes in lipid profile as well. Despite the short duration of this study, however, the results show a clear relationship between carbohydrate intake and thiamine status; one that would likely be magnified over time and certainly if other life stressors and medical and environmental toxicants were added to the mix.

It is important to note current dietary guidelines suggest carbohydrate consumption should fall between 45-65% of total calories, percentages which, per this study would decrease thiamine availability significantly. From the baseline diet to the 55% adaptation phase, thiamine dropped precipitously, only to drop even further at the 65% phase. A recent study surveying macronutrient consumption showed that average carbohydrate consumption across the US population represented approximately 50% of total caloric intake. Importantly though, the study found that 42% of the carbohydrate consumption came in the form of what researchers termed ‘low-quality carbs’ e.g. sugary processed foods with no nutritional value. Thiamine is only found in pork, beef, wheat germ and whole grains, organ meats, eggs, fish, legumes, and nuts. It is not present in fats/oils, polished rice, or simple sugars, nor are dairy products or many fruits and vegetables a good source. Indeed as mentioned previously, some fruits and vegetables may contain anti-thiamine factors. A diet that is 42% empty calories, that contains limited to no nutritive value, save except what has been added post hoc via enrichment, begs for mitochondrial damage and the illnesses that ensue. And yet, that is precisely the nutritional landscape in which most of us exist.

Admittedly, both studies were very small, but the research connecting thiamine deficiency to ill-health and carbohydrate consumption to thiamine loss is clear. Given the dominance of ultra-processed carbohydrate-dense foods in the modern diet, is likely that high-calorie malnutrition underlies much of the chronic illness that plagues western medicine. To learn more about thiamine deficiency and the havoc it wreaks on health: Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition.

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Carbohydrate Addiction

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With the nutrition wars going on (explained well here), recommending the key macronutrients and their proper proportions for our health, the two dominant camps that have emerged are the carbohydrate proponents and those that oppose the consumption of carbohydrates—some oppose only in “excess” (low carbs, ketogenic, Atkins, etc.,) and others “completely” (zero carbs). Between the members of these groups, angry words are exchanged, and competencies, educations, and other personal nonscientific arguments are bandied around. I call this nutrition bullying. And then there are the substantive conflicts and inconsistencies. Like the following confusing statements – 10 pages apart in the National Academies of Sciences Dietary Reference Intake (DRI) guideline book.

In the chapter titled Clinical Effects of Inadequate Intake on page 265 the opening statement is as follows:

“The Recommended Dietary Allowance (RDA) for carbohydrate is set at 130 g/d for adults and children based on the average minimum amount of glucose utilized by the brain.”

Going to page 275 in the same chapter, we read:

“The lower limit of dietary carbohydrate compatible with life apparently is zero, provided that adequate amount of protein and fat are consumed”.  

As you can see: on the one hand, dietary carbohydrate is needed for the brain, and on the other hand, the carbohydrate need is zero for life (thus, zero for the brain). If we had a third hand, I would like to hold in it the USDA recommendations passed on to all nutritionists, suggesting that the ideal carbohydrate intake is 45-65% of the daily Calories. For a typical 2000 Calorie diet (as it is on all food labels) this comes to 225 – 325 gr carbohydrates a day. Thus, we are told that the human body needs zero carbohydrates to stay alive, provided that fats and proteins are consumed in adequate amounts, and also that the RDA is 130 gr carbohydrates for the use of the brain that needs no carbohydrates, while the USDA recommends 225 – 325 gr carbohydrates. Major confusion! Even worse, this confusion is not well known; it goes unnoticed by almost all scientists, dietitians, and nutritionists—not to mention the general public. I would like to shed some light to the sources of this confusion, hopefully providing you with much needed clarity on this hot subject.

Let the Carbohydate War Commence

From an academic perspective the war makes a lot of sense. After all, those who have supported the high carbohydrate paradigm of the Standard American Diet (SAD) have built their careers on its credibility. Whether they themselves follow the recommendations of the SAD or not, they have a vested interest in maintaining their stand in the high carbohydrate field. Similarly, those whose lifelong research has been in the low or zero carbohydrate fields have a vested interest in sticking to their guns.

Those not members of either camp (many scientists, nutritionists, and almost all people in general) can be forgiven for feeling like spectators on the sidelines of a tennis match, during which one’s head ends up spinning from looking left and right nonstop. Many people decide to just jump head first in and test the waters to see where they end up. This causes a lot of problems because macronutrients represent life sustainment and are not up for games and self-experimentation—people can get hurt. Each macronutrient has its very specific quality. Some are necessary for the body to keep it healthy and others are not needed at all or can even be harmful. An educated choice is a better approach but beyond the above described controversy, there is much misinformation on the internet, creating further confusion.

Macronutrient Choices: What They Do and Do Not Do

There are three macronutrients: carbohydrates, proteins, and fats.

Carbohydrates

Carbohydrates are all plant matter: all fruits, vegetables, nuts, seeds, and grains. While many people think that vegetables, fruits, and whole grains are “not carbohydrates”, only sugar and desserts are “carbs”, in reality, all carbohydrates turn into sugar in our bodies. In this sense, there is very little difference between eating 4 grams of sugar from a teaspoon or 4 grs sugar equivalent from an apple or a slice of bread.

Carbohydrates can be “free glucose”, such as the teaspoon of glucose or the amount of glucose in a fruit, or they can be attached to fiber and need separation, or to other carbohydrate forms that need to convert to glucose, such as fructose, starches, galactose, or lactose. Those carbohydrates that need any type of conversion by the body into glucose are not listed as “sugar” on product labels. In general, on every food label you find sugar (free glucose), fiber, and carbohydrates. Since fibers don’t convert to sugar, to find out the total amount of sugar that will become active sugar in the body, we need to subtract fiber from total carbohydrates.

Here is an example to help you understand what I mean: take a slice of unsweetened whole wheat bread from the USDA database. You will see the following on the label and in [] are my explanations:

Carbohydrates by difference: 12.11 gr [total carbohydrates]
Fiber: 1.7 gr [both soluble and insoluble]
Sugar, total: 1.23 gr [free sugar].

We know that a slice of unsweetened wheat bread like this doesn’t taste sweet, yet, if you subtract the fiber from the total carbohydrates, the actual sugar amount in the slice of whole wheat bread is 12.11 – 1.7 = 10.41 gr. This amount truly represents everything that is either glucose or that converts to glucose in the body and not only the sweetness value the slice of bread has by its free sugar content. The actual sugar amount for the bread is 10.41 gr, or almost 3 teaspoons of sugar, in a food item that nobody considers sweet.

Every single carbohydrate item you can think of provides mostly sugar to the body in terms of macronutrients—very little protein and fat. Carbohydrates can also provide micronutrients, such as vitamins, minerals, and various antioxidants, plus fiber. However, we must remember that, according to one of the above quotes, supported by the real-life experiences of many ethnic/tribal societies and those individuals who have followed a carb free diet, carbohydrates are not essential for life at all. We can completely live a healthy life without a single slice of bread, without a single apple, or any other carbohydrates. How about the micronutrients in carbs and fiber: do we need those? The answer must be “no” if we have zero need for carbohydrates—therefore, carbohydrates are not an essential macronutrient.

Proteins

Proteins are mostly in animals and seafood. I created a table listing all amino acids—proteins are made from amino acids.

Amino Acids
Amino Acids

We have two types of amino acids: essential and non-essential. Within the non-essentials, most are glucogenic (meaning they convert to glucose), and one can be converted either to glucose or to ketones. Among the essential amino acids, three can only convert to glucose, two only to ketones, and four to either. Two questions should pop into your mind immediately: 1) Is there a reason why some of the amino acids convert to glucose and others to ketones and 2) why do we have amino acids that only convert to ketones? The answer is quite simple: the body can use two fuels for energy: glucose and ketones and it needs to have the ability to move between these two metabolic processes seamlessly. Thus, amino acids that can only be used as ketones, can be used by our body very well. The reason for some to only convert to ketones is that some cells in the body (including the brain that controls Parkinson’s disease1 and Alzheimer’s disease) work better and improve while using ketones.

Lastly, plants contain little protein compared to animal/seafood sources, therefore, those with a mostly vegetarian or vegan diet are greatly disadvantaged in the essential amino acid category.

Fats

The third macronutrient class is fats (fatty acids). Fatty acids are found is all animal sourced foods, including seafood and, in some carbohydrates—not all. Unlike carbs or proteins, all fats are essential. We typically discuss fats as saturated, monounsaturated, and polyunsaturated fats, but in reality, these three fat types are always found together in nature, so it is best to discuss fats from the perspective of what type of omega fats they are. There are several but the most well-known are omega 6 and 3. Omega 6 can be found mostly in plant-based foods and some in animal fatty acids, and omega 3 is in mostly animal/seafood sourced foods. There are three types of omega 3 fatty acids: ALA (from plants only), EPA and DHA (from animal and seafood only). The human brain is over 60% fat, much of it is DHA (EPA is a precursor to DHA) and since that is only found in animal/seafood sources, eating meats and seafood is essential. Those who get their omega 3s as ALA from carbs are in trouble, because the human body is not capable for quantity conversion of ALA to EPA or DHA. This causes some major problems for vegetarians and vegans—males and females differ slightly in conversion rates2,3.

Are We Eating Foods or Drugs?

You are thinking “how silly is this question? Of course, we are eating foods.” Hold that thought. We need to understand the hormonal connection to be able to answer the question if certain foods can be drugs. If we eat something that is not needed for our life and survival, such as a carbohydrate, what role will it play? There is a battle going on inside your body as you eat; the battle of hormones, how macronutrients affect them, and how your brain reacts to what you eat. This is currently a highly controversial topic between the two warring camps of scientists. I want to present here some of the arguments in this debate.

Let’s talk about hunger and what drives hunger considering the macronutrients we discussed—focusing on carbohydrates, the subject of the most heated debates.

A scientist colleague, Dr. David Pendergrass, describes what food is and what it does in terms of our metabolic and endocrine (hormonal) system very eloquently on his blog:

“Clearly carbohydrates are not drugs in the same way that heroin is. They are indeed nutrients. Yet they activate the dopaminergic mesolimbic pathway (so called rewards or saliency pathway depending upon the neurobiologist you happen to be talking to…), in the same way heroin, nicotine, and alcohol do. To that end…, it has drug-like capacity. The neurobiologist perspective to addiction is that down-regulation of receptors MUST occur and that withdrawal syndromes occur. Heroin and opiates are addictive under that qualification as the opiate receptors downregulate via intracellular Ca++/phosphorylation events, decreased receptor expression and receptor withdrawal mechanisms…So by this definition, carbohydrates may indeed be considered addictive because of the insulin receptor down regulation (AKA insulin resistance) that occurs with chronic hyperinsulinemia. Since insulin is considered an anorexogenic peptide, then you would need progressively more carbohydrate to induce satiety as more and more insulin is needed to bind to insulin receptors to achieve the same results. This particular description might well merit the term addiction in the down-regulation sense.

Addiction by a behavioral definition is different. It suggests that anything drugs (carbs, alcohol, sex, gambling, food) that is patently ‘bad-in-excess’ or to the point that it affects health or work or relationships and is difficult to stop, would be an addiction by psychologists. In these cases, there is neuronal reinforcement of the behavior by the compulsion. This neural plasticity is accompanied by specific changes in neurotransmitter release and receptor organization across the synapse. Indeed, increased numbers of synapses occur with such compulsions. Again, this is a function of the behavior-causing neuronal rewiring in the dopaminergic mesolimbic pathway that supports the compulsion. In this manner and definition, carbohydrates by a psychological definition would also be considered addictive.”

It is important to recognize the differences between – let’s say – opioids and carbs. The process of down-regulation, the reduction in receptors in numbers and sensitivity, takes significantly longer for carbs, allowing for the development of a chronic condition we know as type 2 diabetes, considered to be a terminal chronic disease if left untreated. Actually, type 2 diabetes can be reversed in most cases—this is a subject for another article in the future. Studies show that some foods—those with high glycemic index (GI)—seem to activate those reward pathways in the brain that are also activated by street drugs. Furthermore, ghrelin, a hormone involved with hunger and satiety is also involved with the reward brain circuit in both food and drug-induced reward mechanisms.

In any case, both with street drugs and carbs, the receiving hormone or neurotransmitter (in the brain) loses its receptors or their sensitivity to deliver the drug or carbs to the target cells4. With such identical mechanisms and ultimate consequences, eating carbohydrates suspiciously looks like an addiction. Furthermore, we must ask what makes quitting carbohydrates so difficult. Many people struggle to quit—often quitting for some time and then returning, unable to hold sweet-free life. This table, “relative sweetness value”, shows some really scary numbers. Natural sugars, such as sucrose and fructose, are significantly sweeter than glucose by taste—is sweetness the driving factor? Apparently, it may just be so5. It is worthy to note that while fructose is the sweetest of all natural sugars at 110 in relative sweetness factor, glucose is only 74, so there is a significant difference between them—compare this to lactose in milk at 16. Aspartame, a very common sugar substitute has a relative sweetness factor of 18,000! Wow! If relative sweetness value alone drove sugar addiction, then sugar substitutes would elicit an addiction as well—and indeed they do. “Intense Sweetness Surpasses Cocaine Reward.” And while my initial hunch was that since fructose has a higher relative sweetness value than glucose, it would elicit a higher reaction in terms of addiction, this is not the case. A specific scale, the Yale Food Addiction Scale (YFAS) was developed to assess food addiction.

From an evolutionary standpoint, getting addicted to something is not a good thing as withdrawal (withdrawal is a necessary component of addiction) produces weakness and works against the survival of the fittest. In the long history of human evolution, glucose/fructose were not available in big quantities, and so addiction danger was never present. This also immediately implies that because of the short/seasonal availability of glucose and fructose, it would have created an evolutionary advantage to those whose carbs cravings was strong and could gobble up all that was available when it was available. Therefore, what we now label as addiction, at one time may have had a different role and vastly different manifestation—without withdrawal—serving as a benefit to human kind. Research also found that reactive hypoglycemia (RH), a form of insulin resistance where glucose levels drop drastically after eating, initiate a different brain response from those subjects without RH. RH subjects seek higher carbohydrate and caloric content foods. In addition, there are “brakes” in the intestines and the gut area of human. Such brakes serve to cause satiety or hunger, which is based on factors of BMI, age, and gender.

Only in the very recent past have been high glucose/fructose containing foods and drinks readily available. Over-consumption of highly sweet carbohydrates don’t activate our satiety hormone (ghrelin) the same way as protein or fat does. “[G]hrelin activates an important reward circuit involved in natural- as well as drug-induced reward, the cholinergic-dopaminergic reward link”. It also appears that co-factors are involved: people with higher level of alcohol consumption may crave more sweets and those with higher consumption of sweets may crave more alcohol.

There is much more research needed to understand the exact mechanism of sugar and sweet carbohydrates cravings, though it seems clear that highly processed, fast-absorbing carbohydrates share pharmacokinetic properties with drugs of abuse. While sugar or processed carbohydrates are not likely to be classified as drugs in the near future, further evaluation for what they do to the human body is warranted, particularly given the obesity and metabolic syndrome crisis we are facing. As stated all through, carbohydrates—including both highly processed and non-processed types—are not essential for us to eat.

The biggest question we need to ask is how can something that takes up such a large percent of our caloric intake – and does so unnecessarily – be ever eliminated from our diets. Should carbohydrates be regulated by taxation and advertisement controls similarly to tobacco and alcohol? Or are we ready to continue long-term chronic disease treatments at astronomical costs because eating carbohydrates is so culturally ingrained?

Sources

1             VanItallie, T. B. et al. Treatment of Parkinson disease with diet-induced hyperketonemia: A feasibility study. Neurology 64, 728-730, doi:10.1212/01.Wnl.0000152046.11390.45 (2005).
2             Burdge, G. C., Jones, A. E. & Wootton, S. A. Eicosapentaenoic and docosapentaenoic acids are the principal products of α-linolenic acid metabolism in young men. British Journal of Nutrition 88, 355-363, doi:10.1079/BJN2002662 (2002).
3             Burdge, G. C. & Wootton, S. A. Conversion of α-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. British Journal of Nutrition 88, 411-420, doi:10.1079/BJN2002689 (2002).
4             Figlewicz, D. P., Bennett, J. L., Aliakbari, S., Zavosh, A. & Sipols, A. J. Insulin acts at different CNS sites to decrease acute sucrose intake and sucrose self-administration in rats. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 295, R388-R394, doi:10.1152/ajpregu.90334.2008 (2008).
5             Murray, S. M., Tulloch, A. J., Chen, E. Y. & Avena, N. M. Insights revealed by rodent models of sugar binge eating. CNS Spectrums 20, 530-536, doi:10.1017/S1092852915000656 (2015).

 

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