Possible Treatment for COVID-19 Hyperglycemia to Improve Patient Outcomes

Possible Treatment for COVID-19 Hyperglycemia to Improve Patient Outcomes

Deborah Barges

December 2, 2020

Pre-publication version.

Chelation of copper may be a treatment to reduce COVID-19 induced hyperglycemia. By reducing oxidative stress, a mild amount of copper chelation could improve COVID-19 outcomes.

Concerning:
Blood glucose on admission predicts COVID-19 severity in all
(November 30, 2020[1])

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High copper from illness has been long recognized, causing anemia, where transfusions helped and adding copper did not - why they did not try chelating copper instead, I don't know.[2]

Zinc is a copper antagonist.[17] When the body is sick, zinc is prioritized to the immune system,[3,4] explaing elevated copper levels during illness.[2]

Copper chelators, such as Trientine, have been demonstrated to treat and even reverse diabetic cardiovascular damage from free radical and loosely bound copper damage in type 2 diabetics[5] and to treat Wilson's disease, a genetic mutation induced copper storage condition.[6]

Many aspects of diabetic related pathologies can be attributed to hyperglycemia-induced copper issues and aceruloplasminemia[7,8], which could apply to the infective stress induced hyperglycemia of coronavirus. Copper has been described as having diabetogenic effects.[9]

This implies that copper chelation may reduce hyperglycemia, and that it therefore should be investigated to see it it improve coronavirus outcomes.

Even if does not directly affect hyperglycemia as relates to predicting coronavirus severity, it is likely the body will be able to prioritize more zinc to the immune system it it can free the zinc from its duties of removing copper. Likewise, reducing copper oxidative stress[7,8] from temporary illness induced excess of copper would reduce stress on the body in general.

Between these two mechanisms, there could be an improvement in outcomes for Covid-19, as well as cytokine storms, other severe pathogenic illnesses, and potentially injuries with severe inflammation, as well.

Research to define a sufficient dose to benefit without reducing copper to the point of causing iron deficiency or anemia will be required.

Until then, reducing copper via diet[10] and increasing zinc via diet (beef versus chicken, versus vegetarian meals, and especially high zinc but also potentially high copper seafood in the hospital)[11] should also be investigated.
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Whatever is put into the body must be stored, excreted, or used. If it cannot be stored or excreted, then the body must prioritize other nutrients to use it up in a function preferably where much of the excess can be dealt with with a minimum of loss of other nutrients. Otherwise, damage may result.[12]

Many things affect zinc absorption[20], including different types of zinc absorb differently, citrate being an aid to absorption.[13] Patients who drink citrus fruits in their diet may be getting better absorption, and many people prefer fruit juice with their breakfast. That may affect absorption of zinc supplements in hospitals at night.

Folic acid results in zinc excretion through fecal matter[14,15, 16], and should therefore also be avoided (despite whether from lack of absorption or excretion through the liver.)

Whether dietary folate is a concern, as one of the nutrients along with zinc required for the sense of smell and taste[17], should be reviewed.

The ability to deflect other nutrients may be allowing the body to use these senses as ad hoc zinc storage (to make up for the lack of dedicated zinc storage in the human body[11,18]) in people with better coronavirus outcomes, should be investigated.

Folic acid fortified foods (such as bread, noodles or rice) causing zinc malabsorption or excretion could explain why different studies show that zinc in different quantities is more or less beneficial for Coronavirus, maintaining a debate which would be better for being resolved.[19,20]

The diet of patients in these studies must be considered.

The specific patients chosen for these studies must be looked at, as well, beyond the standard demographics.

People with MTGFR gene mutations[21] (such as some schizophrenics[22]) may have different zinc requirements, depending upon how much folic acid they are ingesting. Likewise, copper overload, Pyrrole syndrome, undermethylation, overmethylation[23] and other low zinc populations need to be grouped demographically separate, because their zinc requirements will be higher.[18(zinc lozenges and variable results),24]

Slow absorption zinc[25] could be beneficial because there is no dedicated zinc storage in the body.[18]

To prevent excessive intake zinc combined with other copper chelators (and when adjusted, reduced folic acid, phytates, and other nutritional elements which interfere with zinc), from causing anemia, testing copper will be necessary.[1,20]

Medications can interfere with nutrients in the body.[28] There is a list in many hospital websites.[30]

If copper is too low[26] or too high[2], anemia or iron deficiency will result. This could be a problem for people trying to protect themselves from Coronavirus by taking too much zinc as well in the hospital. Loss of appetite[27] is one recognizable symptom (and could explain better why anorexia nervosa so commonly happens to young women particularly at the start of menarche[17].) Although usually rare, zinc toxicity (including, at its worst, reduced immune function) could be another home use zinc risk.[20]

Testing for iron deficiency or anemia will not be able to differentiate between the two causes: excessive zinc especially in patients who never had coronavirus, and shortage of zinc in those who were strongly depleted but survived.

In addition, plasma zinc testing should not be totally relied upon, because in experimental human model studies, when zinc deficiency was very mild (3 to 5.0 mg Zn intake while zinc was restricted), the plasma zinc concentration remained approximately within the normal range, decreasing only after 4–5 months. However, lymphocytes, granulocytes, and platelets decreased within 8–12 weeks.[31,32,33,34]

Low magnesium[35] and high iron[36] also may not show in standard serum testing, which suggests that the body wants the brain, heart, and other critical organs to get the proper nutrition. Mild deficiencies may become intracellular, or build less efficient chemicals (low vs high density fibrogen in magnesium deficiency[37]), until more thrifty and efficient genes are located, and epigenes are created. The body is unaware that a doctor is doing serum testing who, given accurate results, will be able to give it the nutrition it lacks.
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In conclusion, copper chelation could be a treatment which would target hyperglycemia as a major factor in coronavirus negative outcomes, by protecting the body from oxidative stress and allowing more zinc to be prioritized to the immune system, and there are other factors that could be considered concerning the correct doses of zinc required to be most beneficial during coronavirus, including dietary choices which might be affecting studies as well as survival rates.

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There is an article on a Wilson's disease diet which is not peer reviewed, possibly because a low copper diet is not considered to be necessary with Wilson's disease for people receiving copper chelation, which is considered the gold standard of Wilson's disease treatment[6], but it also includes a useful list of concerns to explain why results in studies may vary by location as well as region, such as copper in the water supply and metal cooking and eating utensils.[38] Because both researchers and first responders are becoming exhausted, they could use a checklist to work from, if just for reminders and ideas, even if it isn't complete or completely accurate, as long as they know its limitations.

An example of things one might not think of would be whether it is wise for people to wear copper infused gloves, socks and other clothing or supportwear. While the amount of copper absorbed through the skin is probably negligible, caution suggests that if it isn't necessary, patients should consider putting it aside until proving it is not an issue, or until recoverd. If it is enough to be helpful for joint and muscle pains, it may be enough to be harmful, as well.
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Author Contributions:
D.B. performed literature research and wrote this letter.

So far, no one has edited and reviewed the text.

This is a pre-publication version of the manuscript.
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Funding:
There has been no funding.
Conflict of interest statement:
The author declares no conflict of interest.
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I have no affiliations with anyone (more's the pity) except for my website, JOREM, cited only once, and am an independent researcher, studying the one cause of fibromyalgia which I have isolated so far by experience and accident, and the zinc-copper-iron homeostases as a result.
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Footnotes:

1 Blood glucose on admission predicts COVID-19 severity in all
November 30, 2020 (Miriam E. Tucker, MDedge and Medscape)
https://www.mdedge.com/hematology-oncology/journals;
From original research:
Francisco Javier Carrasco-Sánchez, Mª Dolores López-Carmona, Francisco Javier Martínez-Marcos, Luis M. Pérez-Belmonte, Alicia Hidalgo-Jiménez, Verónica Buonaiuto, Carmen Suárez Fernández, Santiago Jesús Freire Castro, Davide Luordo, Paula Maria Pesqueira Fontan, Julio César Blázquez Encinar, Jeffrey Oskar Magallanes Gamboa, Andrés de la Peña Fernández, José David Torres Peña, Joaquim Fernández Solà, Jose Javier Napal Lecumberri, Francisco Amorós Martínez, María Esther Guisado Espartero, Carlos Jorge Ripper, Raquel Gómez Méndez, Natalia Vicente López, Berta Román Bernal, María Gloria Rojano Rivero, José Manuel Ramos Rincón, Ricardo Gómez Huelgas & for the SEMI-COVID-19 Network (2021) Admission hyperglycaemia as a predictor of mortality in patients hospitalized with COVID-19 regardless of diabetes status: data from the Spanish SEMI-COVID-19 Registry, Annals of Medicine, 53:1, 103-116, DOI: 10.1080/07853890.2020.1836566

2 G. E. CARTWRIGHT, M. A. LAURITSEN, P. J. JONES, I. M. MERRILL, M. M. WINTROBE; THE ANEMIA OF INFECTION. I. HYPOFERREMIA, HYPERCU-PREMIA, AND ALTERATIONS IN PORPHYRIN METABOLISM IN PATIENTS. July 7, 1945 (PDF)

3 Martina Maywald, Inga Wessels, and Lothar Rink. Zinc Signals and Immunity. Int J Mol Sci. 2017 Oct; 18(10): 2222.
Published online 2017 Oct 24. doi: 10.3390/ijms18102222
PMCID: PMC5666901
PMID: 29064429

4 Inga Wessels, Martina Maywald, and Lothar Rink. Zinc as a Gatekeeper of Immune Function. Nutrients. 2017 Dec; 9(12): 1286.
Published online 2017 Nov 25. doi: 10.3390/nu9121286
PMCID: PMC5748737
PMID: 29186856
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748737/

5 Garth J.S. Cooper, Yih-Kai Chan, Ajith M. Dissanayake, Fiona E. Leahy, Geraldine F. Keogh, Chris M. Frampton, Gregory D. Gamble, Dianne H. Brunton, John R. Baker and Sally D. Poppitt. Demonstration of a Hyperglycemia-Driven Pathogenic Abnormality of Copper Homeostasis in Diabetes and Its Reversibility by Selective Chelation. Diabetes 2005 May; 54(5): 1468-1476.https://doi.org/10.2337/diabetes.54.5.1468

6 Hedera, Peter; Update on the clinical management of Wilson’s disease. Appl Clin Genet. 2017; 10: 9–19.Published online 2017 Jan 13. doi: 10.2147/TACG.S79121
PMCID: PMC5245916
PMID: 28144156

7 Janet Y. Uriu-Adams, Carl L. Keen. Copper, oxidative stress, and human health. Molecular Aspects of Medicine 26 (2005); 268–298, section 5.1: Diabetes (PDF)

8 Jones CE, Underwood CK, Coulson EJ, Taylor PJ. Copper induced oxidation of serotonin: analysis of products and toxicity. J Neurochem. 2007 Aug;102(4):1035-43. doi: 10.1111/j.1471-4159.2007.04602.x. PMID: 17663749.
https://pubmed.ncbi.nlm.nih.gov/17663749/

9 Watts DL: Nutritional interrelationships — Copper. Trace Elements, Inc., Dallas, Tx., 1988. (unpub), via its reference in: Watts DL: The Nutritional Relationships of Chromium - Trace Elements, Dallas, Tx., 1989 (PDF)

10 Rosanna Squitti, Mariacristina Siotto, Renato Polimanti; Low-copper diet as a preventive strategy for Alzheimer's disease. Neurobiology of Aging, Volume 35, Supplement 2, 2014, Pages S40-S50, ISSN 0197-4580,
https://doi.org/10.1016/j.neurobiolaging.2014.02.031
http://www.sciencedirect.com/science/article/pii/S0197458014003595

11 Zinc - Health Professional Fact Sheet - Office of Dietary Supplements - Table 2
https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

12 Barges, D.; JOREM. https://app.site123.com/about-jorem?w=3290035

13 Milne DB, Canfield WK, Mahalko JR, Sandstead HH. Effect of oral folic acid supplements on zinc, copper, and iron absorption and excretion. Am J Clin Nutr. 1984 Apr;39(4):535-9. doi: 10.1093/ajcn/39.4.535. PMID: 6711464.

14 Simmer K, Iles CA, James C, Thompson RP. Are iron-folate supplements harmful? Am J Clin Nutr. 1987 Jan;45(1):122-5. doi: 10.1093/ajcn/45.1.122. PMID: 3799496

15 D B Milne, W K Canfield, J R Mahalko, H H Sandstead, Effect of oral folic acid supplements on zinc, copper, and iron absorption and excretion, The American Journal of Clinical Nutrition, Volume 39, Issue 4, April 1984, Pages 535–539, https://doi.org/10.1093/ajcn/39.4.535

16 Maria Maares, Hajo Haase; A Guide to Human Zinc Absorption: General Overview and Recent Advances of In Vitro Intestinal Models. Nutrients. 2020 Mar; 12(3): 762.
Published online 2020 Mar 13. doi: 10.3390/nu12030762
PMCID: PMC7146416
PMID: 32183116
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146416/

17 Watts DL: The nutritional relationship of zinc. /. Ortho. Med. 3,2, 1988.

18 Linus Pauling Institute - Micronutrient Information Center - Minerals » Zinc
https://lpi.oregonstate.edu/mic/minerals/zinc, and https://lpi.oregonstate.edu/mic/minerals/zinc#type-2-diabetes-mellitus-prevention (zinc lozenges; variable results by not having copper overload and Pyrrole syndrome, etc [23, 24] in demographics; zinc reducing rate of diabetes - as copper antagonist?)

19 Marina Vogel, Marc Tallo-Parra, Victor Herrera-Fernandez, Gemma Perez-Vilaro, Miguel Chillon, Xavier Nogues, Silvia Gomez-Zorrilla, Inmaculada Lopez-Montesinos, Judit Villar, Maria Luisa Sorli-Redo, Juan Pablo Horcajada, Natalia Garcia-Giralt, Julio Pascual, Juana Diez, Ruben Vicente, Robert Guerri-Fernandez; Low zinc levels at clinical admission associates with poor outcomes in COVID-19. medRxiv 2020.10.07.20208645; doi: https://doi.org/10.1101/2020.10.07.20208645, https://www.medrxiv.org/content/10.1101/2020.10.07.20208645v1

20 Amit Pal, Rosanna Squitti, Mario Picozza, Anil Pawar, Mauro Rongioletti, Atanu Kumar Dutta, Sibasish Sahoo, Kalyan Goswami, Praveen Sharma, and Rajendra Prasad; Zinc and COVID-19: Basis of Current Clinical Trials. Biol Trace Elem Res. 2020 Oct 22 : 1–11.
doi: 10.1007/s12011-020-02437-9 [Epub ahead of print]
PMCID: PMC7580816
PMID: 33094446
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580816/

21MTHFR methylenetetrahydrofolate reductase [ Homo sapiens (human) ]; Gene ID: 4524, updated on 29-Nov-2020
https://www.ncbi.nlm.nih.gov/gene/4524

22 Lin Wan, Yuhong Li, Zhengrong Zhang, Zuoli Sun, Yi He, and Rena Li; Methylenetetrahydrofolate reductase and psychiatric diseases.Transl Psychiatry. 2018; 8: 242.
Published online 2018 Nov 5. doi: 10.1038/s41398-018-0276-6
PMCID: PMC6218441
PMID: 30397195

23 The Walsh Institute - Biochemical Individuality
https://www.walshinstitute.org/biochemical-individuality--nutrition.html
Covered by inurance; one example;
https://askdrgil.com/frequently-asked-questions/

24 Maxfield L, Crane JS. Zinc deficiency. 2020, StatPearls Publishing LLC.

25 Natures Plus High potency sustained-release amino acid chelate magazine 100 mg, 667% daily value. Probably less than one pill daily even with COVID-19; much less otherwise. www.naturesplus.com

26 Meira Fields, Isabelle Bureau, Charles G Lewis; Ferritin Is Not an Indicator of Available Hepatic Iron Stores in Anemia of Copper Deficiency in Rats. Clinical Chemistry, Volume 43, Issue 8, 1 August 1997, Pages 1457–1459, https://doi.org/10.1093/clinchem/43.8.1457

27 Hanin Ghrayeb, Conceptualization, Data curation, Writing – original draft, Writing – review & editing, Mazen Elias, Conceptualization, Investigation, Writing – original draft, Writing – review & editing, Jeries Nashashibi, Formal analysis, Writing – review & editing, Awni Youssef, Project administration, Supervision, Writing – review & editing, Mari Manal, Methodology, Project administration, Liala Mahagna, Methodology, Project administration, Masalha Refaat, Methodology, Project administration, Naama Schwartz, Data curation, Formal analysis, Methodology, and Adi Elias, Conceptualization, Formal analysis, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing, Emanuele Bobbio, Editor.
Appetite and ghrelin levels in iron deficiency anemia and the effect of parenteral iron therapy: A longitudinal study. PLoS One. 2020; 15(6): e0234209.
Published online 2020 Jun 4. doi: 10.1371/journal.pone.0234209
PMCID: PMC7272047
PMID: 32497136
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272047/#:~:text=Iron%20deficiency%20anemia%20(IDA)%20is,the%20major%20regulators%20of%20appetite.

28 Gröber U. Magnesium and Drugs. Int J Mol Sci. 2019 Apr 28;20(9):2094. doi: 10.3390/ijms20092094. PMID: 31035385; PMCID: PMC6539869.
Image on how medications interfere with nutrients:
https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=6539869_ijms-20-02094-g001.jpg

30 Possible Interactions with: Zinc.
St. Luke's Hospital. Lists over 30 medications of five classes which deplete zinc, as well as other types of interactions.
https://www.stlukes-stl.com/health-content/medicine/33/000999.htm

31 Ananda S Prasad; Zinc in Human Health: Effect of Zinc on Immune Cells. Mol Med. 2008 May-Jun; 14(5-6): 353–357.
Published online 2008 Apr 3. doi: 10.2119/2008-00033.Prasad
PMCID: PMC2277319
PMID: 18385818
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277319

32 Prasad AS, Meftah S, Abdallah J, Kaplan J, Brewer GJ, Bach JF, Dardenne M. Serum thymulin in human zinc deficiency. J Clin Invest. 1988 Oct;82(4):1202-10. doi: 10.1172/JCI113717. PMID: 3262625; PMCID: PMC442670.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC442670/

33 Beck FW, Kaplan J, Fine N, Handschu W, Prasad AS. Decreased expression of CD73 (ecto-5'-nucleotidase) in the CD8+ subset is associated with zinc deficiency in human patients. J Lab Clin Med. 1997 Aug;130(2):147-56. doi: 10.1016/s0022-2143(97)90091-3. PMID: 9280142.

34 Beck FW, Prasad AS, Kaplan J, Fitzgerald JT, Brewer GJ. Changes in cytokine production and T cell subpopulations in experimentally induced zinc-deficient humans. Am J Physiol. 1997 Jun;272(6 Pt 1):E1002-7. doi: 10.1152/ajpendo.1997.272.6.E1002. PMID: 9227444.

35 James J DiNicolantonio, James H O’Keefe, and William Wilson; Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis. Open Heart. 2018; 5(1): e000668corr1.
Published online 2018 Apr 5. doi: 10.1136/openhrt-2017-000668corr1
PMCID: PMC5888441
PMID: 29634047
https://pubmed.ncbi.nlm.nih.gov/29387426/

36 Valberg LS, Ghent CN, Lloyd DA, Frei JV, Chamberlain MJ. Diagnostic efficacy of tests for the detection of iron overload in chronic liver disease. Can Med Assoc J. 1978 Aug 12;119(3):229-36.
PMID: 679127
PMCID: PMC1818130
https://pubmed.ncbi.nlm.nih.gov/679127/

37 Lipinski B, Lipinska I. Effect of magnesium on fibrin formation from lower molecular weight (LMW) fibrinogen. Magnes Res. 2000;13(4):233-237.
PMID: 11153893
https://pubmed.ncbi.nlm.nih.gov/11153893/
38 http://m.arizonadigestivehealth.com/?url=https%3A%2F%2Fwww.arizonadigestivehealth.com%2Flow-copper-diet-for-wilsons-disease%2F&utm_referrer=#2823
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Pre-publication version

©Deborah Barges Apr 2019 - Dec 2020 This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).