We are nearly two years into the COVID-19 pandemic. Lives have been lost around the world and the virus continues to mutate with several strains of concern circulating globally. At the time of this writing the Delta variant is responsible for most of the infections in the US and elsewhere, while the Omicron variant is rapidly emerging. Ask anyone who has survived COVID-19 what it was like, and the answers may range from symptoms of a moderate cold to extreme body pain, fatigue, and respiratory distress, landing them in the hospital. This can be a serious illness even in those with good health and no comorbidities. For those with comorbidities, such as type II diabetes mellitus (T2DM), metabolic syndrome, cardiovascular disease (CVD) and hypertension, the risk of morbidity and mortality with COVID-19 increases greatly. This was the case for a close relative who became ill with COVID-19 in March 2021. But instead of COVID-19 taking his life, it saved him. Let me explain.
Brian was over 350 pounds and his health was deteriorating as a result. We knew that he had hypertension and we could only assume that he harbored metabolic disorders and CVD as well, due to his weight. When he got sick with COVID-19, he was treated with early therapies to reduce the viral load and lessen the inflammation. While his symptoms were manageable, he could not maintain normal oxygen saturation on room air alone and needed to use an oxygen concentrator. His fatigue was unrelenting, his lungs hurt with every breath, and his chest felt heavy. For him, past respiratory infections led to bronchitis or pneumonia and we were concerned that he was headed in that direction. Like many people confronting a COVID-19 infection, he did not want to go to the hospital for fear of being put on a ventilator. However, when all therapies that could be done at home were finally exhausted, his wife convinced him to go to urgent care for an exam and a chest x-ray, where he was diagnosed with COVID-19 pneumonia.
At the time of his exam, his oxygen saturation was below 80, which was very dire. He was admitted to the hospital and quickly placed on a five-day recovery protocol that included remdesivir, high-dose steroids, and convalescent serum that he responded to very well. After the five days, he was released from the hospital and referred to his family physician for follow-up care.
Here is where the “COVID-19 saved his life” story comes in. Being in the hospital for five days made him captive to doctor’s orders and extensive lab work. It was discovered during his stay that he had severe T2DM with a blood glucose level over 300 and hemoglobin A1C at 10.1. He was given insulin injections six times a day to bring his blood sugar down. He knew that he needed to make some serious changes—stay on the same path and get worse or commit to dietary and lifestyle changes to get better. He chose the latter and as of this writing he has successfully shed over 120 pounds by following a modified ketogenic diet and getting regular exercise. I am so proud of him for embarking on this journey to better health. He credits his wife with his success as he knows that he couldn’t have done this without her support and participation.
For Brian, a conscious decision was made to improve his health and this decision reduced his total risk of disease morbidity and mortality from all causes. Whatever health issues he confronts in his life he is now better positioned for a positive outcome. Metabolic disorders, CVD, and hypertension can influence how the immune system responds to an acute illness. It is likely that COVID-19 will become an endemic disease despite vaccination so it is important that we address our health issues now to improve the outcome should we get infected with this persistent and ubiquitous virus.
Coronavirus and Metabolic Disorders
The metabolic dysregulation common to T2DM, metabolic syndrome, and CVD creates an imbalanced immune response that can potentiate inflammatory mediators while inhibiting the immune system’s ability to effectively mobilize against an infection (1). The coronavirus SARS-CoV-2 that causes COVID-19, enters human cells via the envelope spike glycoprotein, which is found on the surface of the virus. This glycoprotein binds to the ectoenzyme angiotensin-converting enzyme 2 (ACE-2) located on human cell surfaces to gain entry into the cell for replication. T2DM induces expression of ACE-2 in the lungs, liver and heart, which would allow for enhanced viral replication and contribute to the severity of the infection (2). At its most extreme, this enhanced reaction can result in a cytokine storm that, if not brought under control, can cause multi-organ failure and death. Identifying populations where severe viral disease can advance rapidly, encourages early intervention when a virus occurs. Early identification of those at risk can also allow time for interventional strategies to prevent a serious reaction to a viral infection and halt the progression of chronic disease associated with metabolic disorders.
Metabolic Dysregulation and Inflammation
The mechanisms by which these pre-existing conditions can make a serious viral infection potentially fatal are not fully understood; however, it is known that hyperglycemia activates metabolic pathways that compromise innate immunity, increase oxidative stress, and potentiate tissue damage through uncontrolled inflammation. The innate immune system is the more primitive of the two main systems of immune defense. The other is the adaptive immune system that creates antibodies and immune memory. The innate immune system mobilizes immune cells to the site of infection via the production of cytokines that initiate an inflammatory reaction. Inflammation generates reactive oxygen species that aid in the defense against pathogens; however, if the process goes on too long, tissue damage can occur (2). During a cytokine storm, what starts out as a normal innate immune response accelerates into a flood of inflammation, resulting in tissue damage, capillary leakage, fluid accumulation, sepsis, hypotension, and clot formation. This can be a very dire situation and is associated with serious lung infections like SARS CoV-1 and SARS CoV-2, especially in those who have comorbid conditions predisposing to chronic inflammation (3).
Looking for the Red Flags
Chronic hyperglycemia and insulin resistance are associated with T2DM, metabolic syndrome, CVD, and hypertension. These disorders could easily exist along a continuum ranging from metabolic syndrome to severe CVD as one disorder can lead to the other if the dysfunction is not addressed early. A diagnosis of insulin resistance or metabolic syndrome serves as a warning that trouble is ahead. Evaluating serum or blood spot markers for fasting glucose and insulin, high-sensitivity C-reactive protein (hsCRP), hemoglobin A1c, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) can provide an overview of key markers that reveal metabolic status. According to a report published by the Centers for Disease Control and Prevention in 2017, over 30 million adults aged 18 years or older, or over 12% of the US population, have T2DM. About 25% of that population was unaware that they had diabetes. The link between T2DM and the development of CVD is well established, and it is estimated that 50% of those with diabetes will go on to develop CVD. The prevalence of metabolic syndrome is even higher at 30% of the US population. When we expand these numbers to a global scale, the prevalence of metabolic syndrome is estimated to be about 25% of the world’s population (4).
Metabolic Syndrome and Risk Factors
Metabolic syndrome is a cluster of conditions consisting of increased visceral fat, dyslipidemia, elevated glucose, insulin resistance, and hypertension. This syndrome can be the precursor to T2DM and CVD, and is primarily related to diet, lifestyle and, to a lesser degree, genetics. Overconsumption of simple carbohydrates and processed foods along with a sedentary lifestyle are major contributors. Additional factors that contribute to metabolic syndrome include stress, insomnia, exposure to viruses, overuse of antibiotics, microbiome imbalances, vitamin D and other nutrient deficiencies, and hormone imbalances. Exposure to metal and non-metal environmental toxins, particularly endocrine-disrupting chemicals during key developmental stages, can have far-reaching effects later in life and across generations (5).
Outside of diet and lifestyle factors that can reduce the risks associated with metabolic syndrome, addressing sex hormone imbalances, thyroid dysfunction, managing stress, and supporting adrenal function and sleep can help to rebalance metabolic disorders. Relative estrogen dominance can be associated with an overactive immune response in both men and women. Men who have excessive belly fat will tend to aromatize testosterone to estrogen so they may have higher estrogen levels than their lean counterparts. A 2018 article in Frontiers in Immunology states, “Besides gender, sex hormones contribute to the development and activity of the immune system, accounting for differences in gender-related immune responses. Both innate and adaptive immune systems bear receptors for sex hormones and respond to hormonal cues.” Sex hormones not only regulate the reproductive system, but also direct the development and function of the immune system (6). Balancing sex hormones supports a more balanced immune response.
Stress and Cortisol
Addressing stress and the resulting output of cortisol can also help keep the immune system balanced. While each of us may have our own strategies for dealing with mental-emotional stress, decreasing physiological stressors is also important. Maintaining stable blood sugar, getting restful sleep, avoiding allergenic and inflammatory foods, and addressing gut inflammation can reduce the physiological triggers of excess cortisol. As a glucocorticoid hormone, cortisol’s primary job is to mobilize glucose for energy when we confront a stressor. Increasing blood glucose triggers the release of insulin to usher glucose into our cells for energy. This response was designed to save our lives and provide us with the energy we might need to fight or flee. However, today’s stressors usually do not require a burst of physical energy so that rush of glucose and insulin results in energy storage rather than energy expenditure. If this process is occurring frequently throughout the day, the resulting dysregulation can set the stage for the development of metabolic syndrome. Elevated cortisol also suppresses the immune system leaving us more vulnerable to infections.
Sleep can help to reset the immune system and support a healthy response in the presence of an infection. Sleep and the circadian rhythm are strong regulators of immune cells, and their functions seem to display a synchronous rhythm. Differentiated immune cells peak during the day as they can be efficiently mobilized against a pathogen. Undifferentiated immune cells peak during sleep when the slower adaptive immune response is initiated, allowing for the creation of immune memory. Lack of sleep results in a heightened stress response with increased cortisol and catecholamines. This invokes a non-specific production of pro-inflammatory cytokines, leading to low-grade inflammation (7).
Sleep disorders may contribute to the development of insulin resistance and metabolic syndrome. The converse may also be true in that metabolic abnormalities associated with metabolic syndrome and insulin resistance may exacerbate sleep disorders. There is an inverse linear relationship between weight and sleep time. Lack of sleep and metabolic syndrome both result in a pro-inflammatory state (8).
Thyroid dysfunction occurs in 30% of those with metabolic syndrome and in those without overt or subclinical hypothyroidism, thyroid-stimulating hormone tends to be in the upper end of the range as compared to those without metabolic syndrome. The thyroid sets the metabolic rate, makes proteins, regulates growth, and drives sensitivity to other hormones. Hypothyroidism is associated with increased blood pressure, fasting glucose, total cholesterol, thyroglobulin, LDL and hsCRP, and decreased HDL (9). Though both hypothyroid and metabolic syndrome are independent risk factors for the development of CVD, these metabolic markers are very similar in each disorder. Factors that interfere with optimal thyroid function are elevated cortisol levels, iodine and selenium deficiency, high carbohydrate and low-protein diets, heavy metal and chemical toxicity, and high estrogen.
Microbiome imbalances often result from poor diet and the overuse of antibiotics, which reduce key strains of necessary bacteria. A healthy and diverse microbiome keeps inflammation in check and maintains a healthy mucosal barrier, preventing the excess absorption of lipopolysaccharide or endotoxin, which potentiates systemic inflammation and is a known contributor to the development of metabolic syndrome. As stated in a 2013 article in the Journal of Molecular Endocrinology, metabolic endotoxemia may trigger toll-like receptor-4-mediated inflammatory activation, eliciting a chronic low-grade pro-inflammatory and pro-oxidative stress status associated with obesity, which may result in cardiovascular damage. Toll-like receptors are proteins that play a key role in the innate immune system and are crucial in the defense against pathogenic microbes through the induction of inflammatory cytokines (10). The main cytokines induced are tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL1-beta), and interleukin 6 (IL-6). These cytokines also happen to be increased in insulin resistance and metabolic syndrome (1).
COVID-19 and Beyond
Metabolic syndrome is a complex state that originates from an imbalance between caloric intake and energy expenditure. The body must find a way to store excess energy, which often results in inflammation and metabolic derangement that has multi-system effects. In the face of COVID-19, we are confronted with the immune dysregulation of underlying metabolic imbalances that reduce the body’s ability to mount a healthy and balanced immune response. This results in an over-expression of the pro-inflammatory cytokines TNF-alpha, IL-1 beta, IL-6—the severity of which is often determined by one’s genetic predisposition and current health status.
Beyond the COVID-19 pandemic, the pathophysiology that leads to the development of metabolic syndrome, T2DM, and CVD increases our risk of morbidity and mortality from all causes. This metabolically dysfunctional state alters our physiological and biochemical processes at a very fundamental level with far-reaching systemic effects. How we respond to any physiological challenge will be determined by several inherent factors; however, we do have some control over how we set the stage for a balanced or dysregulated response to a serious viral infection. The cluster of conditions that are part of metabolic syndrome are largely preventable through improved dietary and lifestyle measures coupled with the knowledge of particular risk factors. While we can take personal inventory of our food choices, body weight, and activity level, unless we test for specific blood, salivary, and urine markers, we will not know the extent of metabolic imbalance we may be experiencing.
The risk factors for COVID-19 shed light on the fact that how we take care of ourselves matters, especially in the face of a serious viral infection. There are many factors including age and genetics that can determine our response to a particular virus, and the variables can be many. However, being aware of where we stand metabolically and taking steps to improve our health during these uncertain times is one thing that we can control. Working with a qualified health professional and using appropriate testing to guide this process can be the beginning of better health, now and in the future.
ZRT Tests to Consider:
- Graves DT, Kayal RA. Diabetic complications and dysregulated innate immunity. Front Biosci. 2008;13:1227-1239.
- Bornstein SR, Dalan R, Hopkins D, et al. Endocrine and metabolic link to coronavirus infection. Nat Rev Endocrino. 2020;16(6):297-298.
- Tisoncik JR, Korth MJ, Simmons CP, et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76(1):16-32.
- Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep 2018;20(2):12.
- Heindel JJ, Blumberg B, Cave M, et al. Metabolism disrupting chemicals and metabolic disorders. Reprod Toxico. 2017;68:3-33.
- Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Front Immunol. 2018;9:2279.
- Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463(1):121-137.
- Wolk R, Somers VK. Sleep and the metabolic syndrome. Exp Physiol. 2007; 92(1):67-78.
- Khatiwada S, Sah SK, Kc R, et al. Thyroid dysfunction in metabolic syndrome patients and its relationship with components of metabolic syndrome. Clin Diabetes Endocrinol. 2016;2:3.
- Neves AL, Coelho J, Couto L, et al. Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. J Mol Endocrinol. 2013;51(2):R51-R64.