Obesity, diabetes and COVID-19 severe symptoms

Here are references to some recent research regarding obesity, diabetes (type 2 at least) and COVID-19.   It seems that several aspects of obesity directly increase the risk of severe COVID-19 symptoms - and so the risk of permanent harm or death:
On one hand, it could be argued that repleting all relevant nutrients to ensure good immune function - including vitamin D to achieve at least 40ng/ml 25OHD - will help immune system function in general, but that these excess adipocyte problems will remain.  On the other hand, as far as I know, the problematic behaviour of these adipocytes is generally only observed in patients whose vitamin D levels have been low for years, and remain low.  (Rat studies may be different - assuming the rats were replete in vitamin D, boron and whatever else they need.)  So there's a chance that with nutrient repletion, their potentially destructive role in the immune response will be significantly less than is normally the case.

When wondering why some countries or groups of people within countries have better or worse outcomes with COVID-19, vitamin D and other nutrients are surely an important factor, as are on-average genetic differences between particular groups of people such as ../#haplotypes .   Varying rates of obesity surely play a role as well


This is a cursory discussion of the field and I have no medical training. (../#disclaimer

Robin Whittle rw@firstpr.com.au .   2020-07-18  Last update 2020-07-27 13:00 UTC

The updates/ page lists all the significant updates to these cv19 pages.

To the main COVID-19 page of this site: http://aminotheory.com/cv19/, concerning nutritional supplements - especially vitamin D and boron - for all adults and some children ASAP, so their immune system firstly fight the SARS-CoV-2 virus well, and secondly, if the infection gets to the lungs, will not respond with a dysregulated, overly-inflammatory way which causes the serious harm and risk of death.

Links such as [W] are to the relevant Wikipedia page.

Be sure to read the Disclaimer!




Obesity itself, even after correcting all nutritional deficiencies and excesses, is likely to remain a serious risk factor for harm from COVID-19, due to the activities of fat cells

It is very well known that being overweight or especially obese is a high risk factor for COVID-19 severe symptoms and death.   "Severe symptoms" doesn't just mean having a hard time in hospital.  It almost certainly means microembolisms and perhaps larger blood clots in multiple organs - lungs, brain, spinal cord, heart, liver, kidneys etc. - which can lead to lasting disability. 

There's a lot of talk about the death rate from COVID-19 being no worse than influenza once the true number of people who were infected is known.  While I am not sure this is the case, even if it was, COVID-19 with severe symptoms - and sometimes with few symptoms - leads to a terrible burden of damage due to the hypercoagulative state of the blood which results naturally from the high level of damage (killing and breaking up) of the endothelial cells (the inner lining of blood vessels) especially in the lungs.   No illness before this - with the possible exception of SARS (SARS-CoV) - leaves such a trail of this kind of damage , much of which may be permanent.   I have read many reports from nurses and doctors stating they have never seen anything like this illness.   A 2020-07-08 report on neurological damage even for some people with mild symptoms:

https://academic.oup.com/brain/article/doi/10.1093/brain/awaa240/5868408

Yet for most people, there are few if any symptoms.  The virus itself need not be problem - but it is if the person's immune system is weakened and/or dysregulated to the point of being self-destructively overly-inflammatory.

Obesity correlates with various other conditions associated with severe COVID-19 symptoms.   There's a lot of research concerning these to low vitamin D levels.  I think it is reasonable to assume that, over many years, low vitamin D levels are a significant contributing cause to most or all of the conditions which are considered comorbid with severe COVID-19 symptoms.  Since COVID-19 didn't cause these conditions, they are direct contributing causes of COVID-19 severe symptoms and/or they are results of some other, separate, conditions (including genetic variation between individuals) which contribute both to the development of the condition and to COVID-19 severe symptoms.

While low vitamin D levels surely, to some extent at least, contribute to the development and maintenance of obesity, obesity itself contributes to low vitamin D levels because vitamin D - in its most important blood circulation borne form, 25 hydroxy vitamin D AKA 25OHD - is fat soluble.  So 25OHD which would normally be in the blood (in solution and bound to vitamin D carrier protein) is diverted to adipocytes in fatty tissues all around the body.  There, it may be slowly degraded - so as far as I know little of this is available to be returned to the blood unless the fat is metabolised to produce energy.

So for a given intake of supplementary vitamin D3 plus whatever comes from sun exposure and food (both usually too low to reach the 40 to 60ng/ml 25OHD levels required for good health - see the main page) obese people have less D3 and so 25OHD (D3 is converted in the liver into 25OHD) in their blood than other people.   This is partly due to their bodies being bigger, and so presumably having a greater volume of blood, but it is also due to them having much more fat than usual, with the 25OHD (and I guess the unconverted D3) going there and generally not returning to the blood.

To the extent that low vitamin D levels (25OHD in circulation) drives obesity, and to the extent that obesity drives low 25OHD levels, there is a positive feedback loop where the two conditions drive each other and so are more difficult to escape than either would be alone.

The extra vitamin D needs of obese people needs to be remembered when considering D3 dosage.  See the main page for graphs and discussion of supplementary D3 dosage according to body weight and the resulting 25OHD levels.  ../#2014-Ekwaru and ../#2020-Baker-a .

In mid -July 2020 I knew that obesity was perhaps the biggest single risk factor for COVID-19 severe symptoms and death.

I had been optimistic that if these people could take suitably large D3 supplements to raise their 25OHD levels safely above 40ng/ml (100nmol/l) - and ideally higher, above 60 or so, since this is still far from the 150ng/ml levels where vitamin D toxicity might occur - in the weeks and months before contracting COVID-19, that they would be largely protected from serious symptoms and death.

This was based on the idea that their obesity was only a marginal actual driver of severe symptoms and that the real risk factor was their low vitamin D levels.   However, some of the research I mention below strongly suggests that there are several aspects of obesity itself which directly drive COVID-19 disease mechanisms.  

Obesity is a tough problem.  There's nothing below regarding how to tackle it, other than the assumption that everyone - including especially obese people - really need to get all their nutrients sorted out, because deficiencies in vitamin D and other micronutrients AND excesses of salt and insufficient potassium are extremely common and drive numerous chronic illnesses, including obesity.

Please see the main page ../ for numerous research articles concerning vitamin D and other nutrients and immune system health.

Please see this page at VitaminDWiki for links to research on COVID-19 comorbidities, including overweight and obesity.

Below is a chart I adapted from this article, by extending the scale to 100%:

Relationship between COVID-19 and obesity
Timur Ekiz, Ahmet Cemal Pazarlı 2020-06-04 PDF date
Diabetes & Metabolic Syndrome: Clinical Research & Reviews Volume 14, Issue 5

https://www.sciencedirect.com/science/article/pii/S187140212030165X



These need to be considered in light of the prevalence of overweight and obesity in the general population - which is not provided.  The authors highlight vitamin D supplementation as one of the approaches to be employed fighting COVID-19 in the context of overweight and obesity.

Adipocytes (fat cells) play several roles in COVID-19 severity


Targeting the Adipose Tissue in COVID-19
Alexis Elias Malavazos, Massimiliano Marco Corsi Romanelli, Francesco Bandera, Gianluca Iacobellis. Obesity 2020-04-21
https://doi.org/10.1371/journal.pone.009062

While several aspects of obesity, including the chronic inflammatory response (no-doubt driven in large part by vitamin D levels well below the safe 40 to 60ng/ml levels recommended by MDs and vitamin D researchers - see the main page) probably drive COVID-19 severity, this article explores direct mechanisms resulting from the activities of adipocytes.

Complex interactions occur between the immune system and adipose tissue.  The overexpression of inflammatory adipokines from visceral fat depots can affect the immune response, impair the chemotaxis, and alter the macrophage differentiation.  The imbalance between anti- and pro-inflammatory adipokine secretion from thoracic visceral fat depots, such as the epicardial and mediastinal, can also play a role in the cytokine storm described in patients with severe SARS-CoV2.

Adipokines [W] are cell-signaling secreted by adipose (fat) tissue.  Visceral, in this context, refers to the internal organs.  Visceral fat refers not only to fat in the organs, but in the area of the organs - around the abdomen - AKA belly fat AKA active fat: 

https://www.diabetes.co.uk/body/visceral-fat.html

Thoracic fat is an uncommon term, defined here as "adipose tissue from the right pulmonary artery to the diaphragm and from the chest wall to the descending aorta" - so I think this means fat surrounding the heart.

As you can see from the main CV19 page ../ an overly inflammatory immune response to the SARS-CoV-2 viral infection in the lungs leads directly to the cytokine storm and endothelial cell damage there, which drives COVID-19 severe symptoms directly and via the resulting hypercoagulatory state of the blood.

Interestingly, adiponectin was reported to predict mortality in critically ill (COVID-19) patients upon admission to the intensive care unit.  The innate inflammatory response of the visceral fat depots can cause an upregulation and higher release of inflammatory cytokines such as IL-6.  Excessive pro-inflammatory cytokine release was thought to be the link between visceral obesity and influenza-related severe respiratory complications.  As elderly individuals are at higher risk of COVID-19 complications and poorer outcome, it is worth noting that aging can cause visceral fat accumulation and adipose tissue inflammation and fibrosis.

Adiponectin [W] is a protein hormone involved in regulating blood glucose levels and fatty acid breakdown.  (Fatty acids are fats - and are an essential part of all cells.)  It is expressed primarily in adipocytes but also in muscle and the brain.   Although its 244 amino acid protein sequence is different, its overall structural shape closely resembles that of Tumor necrosis factor alpha TNFα [W]TNFα along with IL-6 (interleukin 6) is one of the several pro-inflammatory cytokines which drive the overly-aggressive immune response which is a crucial part of severe COVID-19 symptoms.

Tocilizumab, Adipokines and Severe Complications of COVID-19
Antonella Fioravanti, Brunetta Porcelli, Lucia Terzuoli, Maria Romana Bacarelli, Sara Tenti Sara Cheleschi.  Clinical Drug Investigation
2020-07-13
https://doi.org/10.1007/s40261-020-00950-2

The first thing which caught my eye in this article was the mention of ectopic adipocytes - fat cells in locations they do not belong.   I had not heard of this.  The reference they give is to the Malavazos article, which doesn't mention them.  These articles goes into some detail:

https://www.sciencedirect.com/science/article/pii/S2211124719303547

The Release of Adipose Stromal Cells from Subcutaneous Adipose Tissue Regulates Ectopic Intramuscular Adipocyte Deposition.  In rats, subcutaneous (beneath the skin) adipocyte progenitor (leads to the creation of) cells and/or stromal (connective tissue cells associated with fatty tissues) could be released into the circulation and lodge at other locations in the body, leading to ectopic adipocytes which the researchers showed were involved in insulin resistance [W] and metabolic disorders [W].  (Ectopic lipid deposition.)

https://www.thelancet.com/pdfs/journals/landia/PIIS2213-8587(19)30084-1.pdf

Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement.  Ectopic fat in the liver and around the heart.
The link between obesity and acute lung injury during infection can be partially explained by the activation of the renin-angiotensin system. It has been supposed that the virus uses an angiotensin-converting enzyme 2 (ACE2)-dependent mechanism of cellular entry; this receptor is also expressed in adipocytes, including ectopic adipocytes within the alveolar interstitial.

Regarding the renin-angiotensin system [W] which regulates blood pressure, and COVID-19, this is one of many articles of interest:

https://www.sciencedirect.com/science/article/pii/S0014299920304659

"alveolar interstitial" means the cells surrounding the alveoli - the tiny air pockets in our lungs where oxygen and carbon-dioxide exchange occurs with the blood.   So it seems that obesity (by implication in this context, but perhaps other conditions too) can lead to fat cells accumulating in the lungs, as well as better known locations in the liver and heart.

I found this article concerning ectopic adipose tissue in the lungs.  (All this is quick searching - a thorough treatise on these matters would take weeks.)

Obesity and SARS-CoV-2: A population to safeguard
Mikiko Watanabe et al. 2020-04-21
Diabetes Metabolism Research and Reviews
https://doi.org/10.1002/dmrr.3325

Growing data suggest that some patients with severe COVID‐19 infection can develop a condition described as “cytokine storm”. Interestingly, excess fat is associated with complement system overactivation, potentially capable of inducing inflammatory sequelae ultimately leading to such complication.

The complement system [W] is part of the innate immune system which enhances (complements) the ability of antibodies and phagocytic (cell destroying) immune system cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane.   With a dysregulated immune response (which caused or at least worsened by vitamin D deficiency), this can damage healthy cells.

Visceral adipose tissue is capable of secreting IL-6, whose levels were found to be retrospectively increased in SARS-CoV-2 non-survivors. 

If the important role of ectopic visceral and liver fat in the pathogenesis of some of the obesity complications is recognized, close to nothing is known about the possible accumulation of adipocytes within the lung, although some evidence suggests its contributing role to pulmonary injury. In fact, preclinical data demonstrated that fat droplets accumulate within the alveolar interstitium in obese diabetic rats, and recent evidence obtained from a small population confirms that subjects with obesity present accumulation of adipose tissue within the lung parenchyma, its presence correlating with the inflammatory infiltrate.


Terminology:

Parenchyma means the main tissue, in this case of the lungs.

The inflammatory infiltrate refers to the set of immune system cells and (I guess) various compounds including cytokines etc. which are present in inflamed tissue, in the lungs in this case, and which presumably cause this infiltration.

Edema, below: swelling caused by excess fluid trapped in the tissue.

We therefore hypothesize that obesity could play a role in predisposing to serious COVID‐19 complications through several mechanisms: systemic chronic inflammation, related comorbidities such as diabetes, increased complement system activation and IL‐6 secretion. Ultimately, excess fat could also lead to the possible presence of ectopic adipocytes within the alveolar interstitial space that may suffer direct viral infection and in turn aggravate the inflammatory infiltrate, therefore contributing to the massive interstitial edema being observed.


Back to the Fioravanti article.

We can postulate that obesity may predispose to the development and progression of the COVID-19 disease through several mechanisms.  Growing evidence demonstrated that adipose tissue is an active endocrine organ and secretes many substances known as adipocytokines such as adiponectin, leptin, resistin, visfatin, chemerin, tumor necrosis factor TNF-α, IL-6, factors of the complement system, growth factors, and adhesion molecules, involved in the regulation of several processes including inflammation and immunity.  Then, an abnormal secretion of adipocytokines from fat tissue can contribute to development of the condition described as cytokine storm which characterized the severe form of SARS-CoV-2.

They then discuss Tocilizumab [W] which is an artificial antibody which binds to and inhibits the IL-6 receptor.  It is used in treating rheumatoid arthritis (RA) [W].

Obligatory sidebar on yet another disease which is associated with - and so no-doubt to a significant extent caused by - deficiency in vitamin D and perhaps other micronutrients

Google Scholar search for:

 "rheumatoid arthritis" "vitamin D"

This shows plenty of articles reporting low vitamin D is associated with RA.

No doubt Tocilizumab is helpful with RA and other such inflammatory diseases. 

Q Why give an expensive, patented, drug before trying to replete the sufferers in all nutrients known to be involved in immune system health, and therefore which can be expected to reduce the excessive inflammation which drives RA?  (Vitamin D, boron, omega 3 fatty acids, vitamin C and others.)

A There's a lot more money to be made by selling drugs like this than from vitamin D or other nutrients.  Also, it gives the doctors and perhaps the patients the impression that they are using a targeted, highly sophisticated, weapon of choice which directly reduces an important aspect of the disease.  

Repeating the search with boron I found an article showing RA patients have half the boron in their blood than controls.  See the boron section of the cv19 page: ../#boron-ra .

Assuming this is valid, it would not be surprising (especially in the context of the research linking low boron to excessive inflammation) if boron supplements helped reduce COVID-19 symptoms, obesity etc. etc.

They state that Tocilizumab treatment reduces the levels of circulating leptin, chemerin, plasminogen activator inhibitor-1 (PAI-1), and fibrinogen, while boosting the levels of adiponectin:

Adiponectin is an adipokine with insulin-sensitizing and anti-atherogenic properties; hypoadiponectinemia [low levels of adiponectin] has been shown to be associated with obesity, diabetes, metabolic inflammatory syndrome and inflammation, also, low serum levels of adiponectin were reported as predictor of mortality in critically ill patients in intensive care units.

They describe the functions of two compounds mentioned above which are produced by adipocytes, with the implication that having extra adipocytes, as in obesity, and especially having ectopic adipocytes in the lungs, would tend to cause worse, more inflammatory, outcomes with COVID-19:

Leptin has pro-inflammatory properties stimulating the production of TNF-α, IL-6, and IL-12 and potential atherogenic effects.  Chemerin is a novel adipokine involved in inflammation (stimulates chemotaxis, macrophages, and dendritic cells, induces the release of IL-6), in coagulation and fibrinolysis; furthermore, elevated circulating chemerin levels correlate with endothelial dysfunction.


Diabetes, obesity and COVID-19 severity

COVID-19 in people with diabetes: understanding the reasons for worse outcomes
Matteo Apicella et al. 2020-07-17  Diabetes and Endocrinology

https://doi.org/10.1016/S2213-8587(20)30238-2

Extra fat impedes ventilation - in normal and mechanically-assisted breathing. 

According to this article, epicardical adipose tissue is the fat depot that exists on the surface of the myocardium and is contained entirely beneath the pericardium [W], thus surrounding and in direct contact with the major coronary arteries and their branches.   This fat surrounding the heart is regarded as a biologically active organ that may play a role in the association between obesity and coronary artery disease (the largest cause of death in the world).

Obesity is associated with immune dysregulation and chronic inflammation that could mediate progression toward organ failure in severe COVID-19 patients.

Myocarditis and cardiomyocyte dysfunction could be worsened by local biological effects of epicardial adipose tissue, a source of adipokines and pro-inflammatory mediators, and the volume of epicardial adipose tissue is directly associated with BMI.

Moreover, ACE2 is highly expressed in the epicardial adipose tissue of patients with obesity. This could promote virus internalisation into the adipocytes and enhance TNFα and IL-6 release

So the fat cells protecting the heart and enclosing the arteries carrying blood to the heart muscles may become infected by SARS-CoV-2 - and this part of the body may be subject to further immune system overly-aggressive inflammatory destructive responses.

Obesity and diabetes are characterised by chronic low-grade inflammation with increased concentrations of pro-inflammatory leptin and reduced anti-inflammatory adiponectin.  Additionally, people with obesity are often physically inactive, more insulin resistant, and with gut dysbiosis, which might increase the inflammatory response to infection with SARS-CoV-2.  Moreover, individuals with obesity have lower vitamin D concentrations, which could also reduce the immune response.  The role of vitamin D supplementation is currently being investigated in ongoing clinical trials.


A dysregulated inflammatory innate and adaptive impaired immune response might occur in patients with diabetes, accounting for the systemic tissue damage and respiratory and multiorgan failure. The cytokine storm is more likely to develop in patients with diabetes, as diabetes is already characterised by low-grade chronic inflammation. Moreover, in the case of high viral load, the capacity to raise an acute immune response might be compromised in patients with diabetes, exposing them to more severe adverse effects.

One study reported
that patients with COVID-19 with diabetes had higher concentrations of inflammation-related biomarkers, such as C-reactive protein, serum ferritin, and IL-6, and a higher erythrocyte sedimentation rate, compared with patients with COVID-19 without diabetes.

"Erythrocyte sedimentation rate" [W] refers to how quickly red blood cells, in the presence of an anticoagulant, settle in a test tube over an hour.    According to medlineplus.gov : "A faster-than-normal rate may indicate inflammation in the body. Inflammation is part of your immune response system.".

Most people have inadequate vitamin D, boron and omega-3 fatty acids.  Adequate levels of these are known to reduce the excessive inflammation which results from immune system dysregulation.  See the main page ../ for more details.

Some other articles regarding obesity, diabetes and COVID-19

I haven't had time to look at these yet.

Commentary: COVID-19 and diabetes mellitus: What we know, how our patients should be treated now, and what should happen next
Angeliki M. Angelidi, Matthew J. Belanger, Christos S. Mantzoros. 2020-04-19 Metabolism

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167295/


Covid-19 and Disparities in Nutrition and Obesity
Matthew J. Belanger, Michael A. Hill, Angeliki M. Angelidi, Maria Dalamaga, James R. Sowers, Christos S. Mantzoros.  2020-07-15 NEJM

https://www.nejm.org/doi/full/10.1056/NEJMp2021264


A brief analysis and hypotheses about the risk of COVID-19 for people with type 1 and type 2 diabetes mellitus
Charalampos Milionis, Stella Olga Milioni 2020-07-20
Journal of Diabetes & Metabolic Disorders

https://link.springer.com/article/10.1007/s40200-020-00592-3


COVID-19 pandemic, coronaviruses, and diabetes mellitus
Ranganath Muniyappa, Sriram Gubbi 2020-04-26
Endocrinology and Metabolism

https://doi.org/10.1152/ajpendo.00124.2020


COVID-19 and ethnicity: A novel pathophysiological role for inflammation
Abhinav Vepa et al.  Diabetes Metab Syndr 14(5):1043-1051 2020-06-30
https://pubmed.ncbi.nlm.nih.gov/32640416/


Obesity and Higher Risk for Severe Complications of Covid-19: What to do when the two pandemics meet
Alessandra Valerio et al. J Popul Ther Clin Pharmacol 27(S Pt 1):e31-e36  2020-06-29.
https://pubmed.ncbi.nlm.nih.gov/32650354/




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