Metabolic Basis of Disease and a Nutritional Solution

We are facing a significant physician shortage by the year 2030. This shortage will be accelerated with vaccine mandates as there are fewer physicians getting vaccinated than the AMA reports. In order to maintain access for the growing number of aging Americans and increasing prevalence of chronic disease, it behooves the government to relax their stance on these mandates in order to maintain reasonable access to medical care for the population. It should be concerning to all that many American’s health condition is in an uncontrollable free fall. When we evaluate our contemporary treatment strategies for chronic disease, from a bird’s-eye view, it becomes quite evident that our efforts are failing. My interpretation of this failure has to do with the inadequate education in understanding pathophysiology and health, in general. Physicians are not formally educated to understand healthy states, we are educated to understand disease states and how to intervene. Our patients seek our service after their disease process has reached an intolerable threshold; then, in most scenarios, we prescribe a treatment to achieve a condition of “less disease,” not reverse its course. Because our education focus is on disease and not health, we are unequipped to provide the ultimate benefit to our patients — restoration of health. 

With the copious and rushed amount of information required to cover in the first two years of medical school didactics, it is impossible to ensure material mastery, or even reasonable competence. Scholastic achievement in medical school encourages rote memorization, not comprehensive understanding. Intoxicated by the allure of obtaining a degree that will lead to a career of fulfillment and a lifestyle of abundance, the former being a fallacious fantasy, the medical educational paradigm often goes unchallenged. Acknowledging and correcting the shortcomings of our discipline will ultimately improve the health and wellness of our patients. Instead, our approach has contributed to slowing disease progression by oversimplifying disease pathology and following some futile metrics with little insight into detailed understanding of pathophysiological processes.

As an example, the standard lipid panel, which includes LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides is a useless laboratory panel. Colloquially, we know LDL (low density lipoproteins) as the “bad” cholesterol and HDL (high density lipoprotein) as “good” cholesterol, but this understanding is profoundly oversimplified.  Patient’s are instructed that they want to lower their total cholesterol, LDLs and triglycerides, while increasing their HDLs. LDL cholesterol has been identified microscopically in arterial atheromatous plaques and therefore recognized as “bad.” In actuality, LDL cholesterol is vital in providing necessary components to the cellular phospholipid bilayer as well as precursors for production of steroid hormones. Low density lipoproteins provide a package for lipophilic material to be transported in an aqueous medium to peripheral tissues and deposit triglycerides and cholesterol to the cells to maintain membrane fluidity, provide energy and supply metabolic precursors. When we order these labs, they are returned to us in weight-based units (mg/dL), but this tells us nothing about the QUALITY of this important blood component. As it turns out, LDL particle size and number is much more important in determining its pathophysiologic risk, than simply obtaining its weight per unit volume. Increased residence time in the blood also would increase its susceptibility to advanced glycation and oxidation, rendering these particles more pathologic and driving atheroma (clot) formation.  

HDL cholesterol is considered “good” because their function is to scavenge cholesterol and phospholipid byproducts and deliver it back to the liver for excretion through the bile acids. Interestingly, our terminal ileum (last portion of our small intestine) resorbs 95% of the bile secreted for emulsification of fat during digestion. If cholesterol was detrimental to our survival or health, the body would not design a robust mechanism for resorption. Cholesterol ester transfer proteins are involved in transfer of cholesterol and triglycerides between VLDLs, IDLs, LDLs and HDLs, making our simplistic version of LDL “bad”/HDL “good” hypothesis more complex and unlikely. Oversimplifying the complexity of lipid and cholesterol metabolism has come at a detriment for the patients that we treat. Sadly, most clinicians do not understand cholesterol metabolism beyond this simplified version.

Another common disease process that is poorly approached and mismanaged is type II diabetes. Type II diabetes mellitus is the predominant form of all diabetic patients (90-95%). Type I diabetes, is characterized by destruction of pancreatic beta cells (where insulin is manufactured) and absence of insulin production, requiring exogenous (derived externally) insulin administration to provide glucose to the cells for energy. In contradistinction, type II diabetes is a pathophysiological state resulting from hyperinsulinemia (too much insulin) and desensitization of peripheral tissue to insulin resulting in hyperglycemia (high blood sugar). Contemporary treatment options include insulin sensitizing agents (metformin, rosiglitazone, pioglitazone), secretagogues (glimepiride, glipizide, glyburide, repaglinide, nateglinide), or exogenous insulin. Adding insulin to an already hyperinsulinemic state only encourages the body to “hide” excess sugar into the intracellular compartment, evading detection of our testing methods. This provides no health benefit whatsoever, but it “appears” that our biological milieu has improved, when it has only gotten worse. This is equivalent to telling a child to clean their room and them stuffing all of their toys under their bed to avoid detection.

Overabundance of sugar, over decades, contributes to the body naturally trying to rid the body of excess sugar and regain homeostasis. Excretion through the urine is the easiest way, but pharmacologically, we inhibit this mechanism and drive more glucose into cells that don’t need it. This only leads to production of advanced glycation end products and non-enzymatic glycosylization of proteins within the cell. The introduction of high-fructose corn syrup into our diets in the 1970’s contributed heavily to the increase in diabetes and obesity epidemics that we are now suffering from today.  Fructose, unlike glucose, can only be metabolized in the liver and has a distinctly different pathway of catabolism than glucose. During the metabolism in the liver, fructose has three destinations: 3-phosphoglycerate, 2-phosphoglycerate or glycerol.  3-phosphoglycerate and 2-phosphoglycerate can be utilized in the glycolytic (breakdown of sugar) pathway to create energy, but when energy is abundant, glycerol is the predominant end product.  

Glycerol provides the backbone from triglycerides and is intimately associated with VLDL (very low density lipoprotein) production (high triglyceride to cholesterol ratio).  As the body is bombarded with fructose and cannot keep up with the production of VLDLs, the liver accumulates triglycerides and leads to a condition known as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). Development of NAFLD further worsens the insulin resistance of the body and this condition is closely associated to development of diabetes. An abundance of VLDLs being produced by the liver in response to large intake of fructose leads to numerous, small, dense LDLs as the triglycerides are dispersed to the fat tissue, leaving cholesterol in the LDLs. These small, dense LDLs, in the presence of hyperinsulinemia, drive the oxidized LDLs into the arterial walls, creating atheromatous plaques, leading to carotid artery stenosis, coronary artery disease, heart attacks, vascular dementia, strokes, etc. There are numerous other pathological states that fructose catabolism leads to, but this is the most significant.

Most readers will not follow the complexity of these biochemical and pathophysiological pathways, and that is not my intent; rather it is to highlight that we are unable to appropriately treat these diseases through broad generalizations or simplifications. Complex problems don’t always necessitate complex solutions. It is quite evident that our food source is the culprit, contributing to our declining health. Calorimetry oversimplified the idea of fattening and assumed that our bodies functioned similar to rudimentary combustion chambers. Without understanding hormonal influence on fat deposition, simple calorie excess was thought to be the cause of obesity. Until relatively recently, we have started to understand that fattening is not a simplified mathematical equation.  Michael Pollen, in his book “In Defense of Food,” discussed the Standard American Diet (SAD) as containing an abundance of “edible foodlike substances.” Hormonal influence has a profound effect on fat deposition; men and women have far different fat deposition patterns. Men typically deposit fat in the gut and around the viscera (abdominal organs), where women tend to have fat depots in their hips, buttocks and breasts. Our country has faired very poorly in health since the introduction of synthetic food into our diets. However, it is suggested that more synthetic food is our best option. Pharmaceutical companies have taken advantage of this situation and introduced medicine to disguise symptoms without solutions for disease reversal. Currently, there is no financial incentive to create a population of healthy people. Keeping people sick has been lucrative for many businesses and there is little desire for change. Empowering the general public through education and encouragement is where we should start. Eating real food, not marinated in pesticides or genetically modified for more appealing taste and appearance, should be our focus.