Over the last few months, I have written a number of white papers on thiamine for contract. They may or may not be published in part or in full at some future date. Among them, I was contracted to write separate papers about thiamine in diabetes, cardiovascular disease, and Alzheimer’s disease. As I began writing the first article, I realized that these were not separate topics. Rather, each disease process was simply a different manifestation of the same core problem: persistent hyperglycemia. This, in turn, was a direct response to our current ultra-processed, chemically-laden, refined sugar, garbage-food environment; a problem we all seem reticent to confront.
The garbage foods that we consume lead to metabolic dysfunction marked by, among other things, hyperglycemia. Hyperglycemia, in turn, leads to specific metabolic adaptations that result in the inability to efficiently convert consumed foods, not just sugars, but amino and fatty acids as well, into energy. (See here for details.) Poor energy metabolism then drives cravings and overeating as a compensatory reaction to increase metabolic energy, which in turn, further entrenches hyperglycemia and its metabolic cascades. It is a deadly spiral, the likes of which are evident in skyrocketing rates of metabolic ill-health. A recent study found that only 12% of the population, 20% if the authors were generous in their description, could be considered metabolically healthy.
From my perspective, it is this shift in metabolic capacity, in the pathways used to metabolize food that drives much, if not all, modern illness. Importantly, many of the disease processes we now consider to be separate entities, like diabetes, the various cardiovascular diseases, the neurodegenerative diseases like Alzheimer’s and dementia, cancer, and even the litany of chronic autoimmune, inflammatory, or pain and fatigue related disease processes, may not be separate at all. They may just represent the way the consumption of ultra-processed foods and the resulting hyperglycemia mix with the individual’s unique genetic and environmental circumstances to form disease. In other words, food provides the spark, hyperglycemia is the kindling, and how and where the flame burns is determined by the individual’s genetics and the totality of his or her life, lifestyle, and environmental exposures. It all begins with food though.
What Are Ultra-processed Foods?
Just about everything in the middle aisles of a super market or purchased from a fast food establishment would be considered ultra-processed. These products are:
…formulations of several ingredients which, besides salt, sugar, oils and fats, include food substances not used in culinary preparations, in particular, flavours, colours, sweeteners, emulsifiers and other additives used to imitate sensorial qualities of unprocessed or minimally processed foods and their culinary preparations or to disguise undesirable qualities of the final product.
In other words, most of the American diet. These products are highly palatable, densely caloried (because of all of added sugars and fats), and loaded with synthetic chemicals, but have no discernable endogenous nutrient content. Sadly, almost 60% of the American diet for adults and close to 70% for kids aged 2-19 years is comprised of ultra-processed food products.
Processing is not the only problem though. Conventionally grown and raised food and livestock have all but bred out of their products any semblance of nutrition in favor of bigger, faster-growing, and more attractive products. In the place of nutrients, we get excess sugars (yes, conventionally grown produce has a higher sugar content than organic or that grown in the past), along with lots of herbicides, pesticides, hormones, antibiotics and veritable laundry list additional mitochondrial poisons. From farm to table, the composition of modern food products is lacking nutrients while rich with potential anti-nutrient and toxicant compounds. Is it any wonder only 12-20% of the population can be considered metabolically healthy or that hyperglycemia drives modern illness?
Backing up just a bit, let us talk about how discussions of hyperglycemia are framed conventionally and what that has to do with the composition of the foods we ingest. Most discussions of hyperglycemia involve either the absence of sufficient insulin as in the case of Type 1 diabetes or a developed resistance to insulin as in the case of Type 2 diabetes. In either case, there is insufficient insulin available, either absolutely or relative to need, to transport glucose from the bloodstream into the cells and this results in hyperglycemia. Much of the research involves defects in pancreatic islet cell function, glucose receptors and transporters relative to these diseases. In general, diet exacerbates hyperglycemia. With type 2 diabetes, however, diet accounts for almost all of the disease process itself. In many, but not all cases of type 2 diabetes, diet also induces obesity and may provoke a host of additional disease process affecting the heart and the brain. Indeed, Alzheimer’s disease is now considered an outgrowth of persistent hyperglycemia and has been categorized as type 3 diabetes.
This linkage of diabetes with obesity leads many to conclude that if the individual just reduces his/her calories and/or increases activity and loses weight, the diabetes, the obesity, and the assortment of other disease processes that ensue, would resolve and/or be prevented. For some this may be true, but if the persistent rates of obesity, despite reductions in caloric intake are any indicator, this aspect of diet is only indirectly related to the disease at hand. My research involving the some of the metabolic pathways associated with hyperglycemia, leads me to believe that hyperglycemia represents more than just an excess of calories, carbohydrate or otherwise, and that changes to pancreatic islet function, and glucose receptors and transporters are simply adaptive response to ailing mitochondrial metabolism. What is causing metabolism to fail? The American diet of ultra-processed food-like products that are high refined sugars, trans fats and chemical toxins, but low in usable macronutrients and micronutrients – that is the root of these illnesses.
Micronutrient Deficiency Underlies Hyperglycemia
Adenosine triphosphate (ATP), the fuel source for cellular function, the energy currency that all organisms require to survive, is derived entirely from food. The foods we eat provide the macronutrients – protein, fats, and carbohydrates, and the micronutrients –vitamins and minerals – that, with a little oxygen, are then processed by the mitochondria into ATP. Absent frank starvation, the key variables in this process are the micronutrients. Thiamine and its activating partner magnesium are especially important because they manage the gates to this process. Micronutrients derived from foods allow for the catabolism of consumed macronutrients so that it may be turned into ATP. Vitamins and minerals fuel the enzymatic machinery that allows energy factory to work. Insufficient micronutrients slow down enzyme capacity (the energy machinery), causing a backup of macronutrients (a supply excess), at the gates. That excess has to be dealt with. Some of it is forced through alternate pathways that, through a variety processes, break down and salvage some of the macronutrients as a way to temper the backup, but most of the excess either just floats around in the blood or is stored in the fat cells. The glucose that floats around in the blood and desensitizes the glucose receptors and transporters and re-regulates pancreatic islet function – that is hyperglycemia. The glucose that is stored as fat – that is obesity.
Those macronutrients that cannot be processed because of absent micronutrients, not only lead to the hyperglycemia cascades and the various diseases processes associated therewith, but their consumption produces little to no energy or ATP and, in most cases, consumes it. In other words, despite ingesting an excess of calories, the mitochondria, and thus the human in which they reside, are starving. If macronutrients cannot get into the factory, the factory cannot produce ATP. The result is cravings and overeating, which no amount of willpower will overcome. This is why a simple reduction of caloric intake, absent recognition of food composition, does not work for many with type 2 diabetes. They are already starved for energy. Proteomic studies in rodents fed comparable diets illustrate this pattern of poor energetic capacity with reduced expression of the proteins involved in energy metabolism and increased expression of those marking oxidative stress and aberrant cell proliferation (cancer pathways).
A Technical Aside
In more technical terms, when the excess sugars cannot be processed via oxidative phosphorylation or through the pentose phosphate pathway – processes that ultimately produce ATP and other important substrates – they are diverted through salvage pathways like the polyol/sorbitol, hexosamine, diacylglycerol/PKC, AGE pathways. This leads not only to decrements in ATP production but the macro- and microvascular cell damage associated with persistent hyperglycemia leading to heart disease and neurological dysfunction.
Similarly, in the absence of sufficient micronutrients, thiamine in particular, the catabolism of branched chain amino acids suffers, resulting in increased branched chain keto acids, especially short and medium chain acylcarnitines. Surplus acylcarnitines then overwhelm the b-oxidation pathway involved in fatty acid metabolism. This, in turn, leads to incomplete fatty acid metabolism (dyslipidemia) and the formation of the pro-inflammatory diacylglycerol and ceramides associated with metabolic dysfunction. The hyper-activation of ceramide synthesis expedites cell death, blocking complex 3 of the electron transport chain in the mitochondria.
Inadequate micronutrient availability, and again, thiamine and magnesium especially, further imperials the alpha oxidation of fatty acids. This is the step before beta-oxidation. Poor alpha-oxidation results in increased phytanic acid and disrupted sphingolipid homeostasis; two patterns with linked with a variety of neurological sequelae. All of this is linked to persistent hyperglycemia, which evolves from inadequate micronutrient content relative to demands.
Coincidently, COVID death is linked to both increased ceramide synthesis and disturbed sphingolipid homeostasis.
We postulate that SARSCoV-2 causes endothelial damage by binding ACE2 and misbalancing the renin-angiotensin pathway, dysregulating sphingolipids and activating the ceramide pathway, known to mediate endothelial cell apoptosis in the setting of radiation damage. Such injury also generates reactive oxygen species, vasoconstriction and hypoxia, and ultimately the deposition of platelets on an exposed vessel basement membrane initiating the intravascular coagulopathy and multi-organ failure, pathognomonic of severe COVID-19 and death.
Underlying both processes are micronutrient deficient patterns of hyperglycemia, e.g. insufficient thiamine, magnesium and likely other nutrients, but most have not been investigated. Inasmuch hyperglycemia accounts for much of the risk for COVID severity, it is difficult not wonder if these pathways were not already entrenched pre-virus and the virus simply escalated the negative adaptations beyond rescue.
Food Composition Matters More Than Caloric Intake
From this perspective, it is clear that it is not solely an excess of calories that causes hyperglycemia, or even an excess of carbohydrates, although both play a large role. It is the quality or composition of the food that is the problem. Modern foods are calorie dense, sure, primarily because of the use of refined sugars and added fats. They are also loaded with chemical poisons, which we all seem to disregard as important. Carbohydrates derived from natural, organic, and unadulterated fruits, vegetables and grains, carry with them vitamins, minerals, fiber, and proteins that allow the body to convert the macronutrient substrates into useable energy. Indeed, a diet rich in these types of foods is unlikely to induce hyperglycemia or obesity. In contrast, processed foods, while high in carbohydrates, fats, and chemicals that are toxic to the mitochondria, carry few to no micronutrients, little to no fiber, or other compounds that can be used by the body to produce ATP all the while carrying an abundance of chemical toxins. From a metabolic standpoint, ultra-processed foods are nothing more than edible poisons. They demand more energy to process than they add and wreak havoc with far more systems than were illustrated here. The hyperglycemia and associated damage that ensues is evidence of this process. If we are to tackle these health issues, the entirety of modern food landscape relative to metabolic health must be addressed.
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