Mild Copper Chelation to Decrease Oxidative Stress, Reduce Hyperglycemia, and Improve COVID-19 Outcomes
Possible Treatment for COVID-19 Hyperglycemia to Improve Patient Outcomes
Deborah Barges
December 2, 2020
Pre-publication version.
Chelation of copper may be treatment to reduce 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[1,2])
High copper from illness has been reported since 1945, causing anemia, where transfusions helped and adding copper did not.[3] (For some reason, they did not try chelating the extra copper.)
Zinc is a copper antagonist.[4] When the body is sick, zinc is prioritized to the immune system,[5,6], and must be prioritized from some other use, explaing elevated copper levels during illness.[3]
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[7,8] and to treat Wilson's disease, a genetic mutation induced copper storage condition.[9]
However, using penacillamine with Coronavirus as a copper chelator could be dangerous, because it interacts with zinc.[10,11,12] All copper chelators must be tested carefully before use, for that reason.
Many aspects of diabetic related pathologies can be attributed to hyperglycemia-induced copper oxidatinve stress and aceruloplasminemia[13,14], which could apply to the infective stress induced hyperglycemia of coronavirus. Copper has been described as having diabetogenic effects.[15]
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[13,14] 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, and thus potentially worsening outcomes, will be required.
Until then, reducing copper via diet by reducing raw foods, avoiding potatoes, nuts, and specific produce and grain products, including high zinc sources such as certain seafood, turkey, beef liver and some organ meats which are also high in copper[8] and increasing zinc via diet in the hospital[16] should also be investigated.
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.[17]
Many things affect zinc absorption[18], including different types of zinc absorb differently, citrate being an aid to absorption.[19] 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[20,21,22], and should therefore also be avoided (despite whether from lack of absorption or excretion through the liver.)
Whether dietary folate or methylfolate are concerns, as other forms of B9, being another nutrient working with zinc required for the senses of smell and taste[5], should be reviewed.
The ability to dispose or store other nutrients required for the senses of taste and smell may be allowing the bodies of people who, losing these senses, have better coronavirus outcomes, by using these senses as ad hoc zinc storage[17] (to make up for the lack of dedicated zinc storage in the human body.[16,23]) This should be investigated further, to see if it can be replicated in a clinical setting, or whether it is dependant on genetic differences, or epigenes which may be impossible to affect in the duration of a patient's illness.
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 and less beneficial against Coronavirus, maintaining a debate which would be better for being resolved.[18,24]
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 MTHFR gene mutations[25] (such as some schizophrenics[26]) may have different zinc requirements, depending upon how much folic acid they are ingesting. Likewise, copper overload, Pyrrole syndrome, undermethylation, overmethylation[27] and other low zinc populations need to be grouped demographically separate, because their zinc requirements will be higher.[23(zinc lozenges and variable results),28] Grouping by these subtypes rather than averaging everyone together will give clear indications of who needs different levels of zinc. These may relate to the subtypes more at risk for Alzheimer's.[8]
Slow absorption zinc[29] could be beneficial because there is no dedicated zinc storage in the body.[23]
To prevent excessive intake zinc combined with other copper chelators (and when adjusted, reduced folic acid, phytates, and other nutritional elements which would otherwise interfere with zinc), from causing anemia, testing copper will be necessary[3,18,30] which, when bad enough, can affect appetite, which might be useful as a diagnostic tool to suggest when iron may be deficient.[31]
Medications can interfere with nutrients being absorbed, stored, exceted or otherwise usable to the body.[32] There is a list of medications known to interact or interfere with zinc on many hospital websites[33] which doctors should be aware of, to possibly adjust zinc levels accordingly.
If copper is too low[30] or too high[3], anemia or iron deficiency can 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 could be be useful for diagnosis[31]; sharing this with the public may be advisable. (This loss of appetite could explain better why anorexia nervosa particularly happens to young women at the start of menarche[3].) Although usually rare, zinc toxicity (including, at its worst, reduced immune function) could be another home use zinc risk, when used for prevention instead of treatment.[18]
Because low and high copper can both cause iron deficiency, testing for iron deficiency or anemia will not be able to differentiate between excessive zinc especially in patients who self-treated but never had coronavirus, and shortage of zinc in those who were strongly depleted during illness but survived with a deficiency.
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.[34,35,36,37]
Low magnesium[38] and high iron[39] 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[40]), 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.
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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Author Contributions:D.B. performed literature research, wrote this letter, and did all the editting.
Corresponding email address: acctdmail@aol.com
This is a pre-publication version of this 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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Deborah Barges is an independent researcher, initially studying one of the causes of fibromyalgia, isolated 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 allNovember 30, 2020 (Miriam E. Tucker, MDedge and Medscape)https://www.mdedge.com/hematology-oncology/journals;
2 Carrasco-Sánchez FJ, López-Carmona MD, Martínez-Marcos FJ, Pérez-Belmonte LM, Hidalgo-Jiménez A, Buonaiuto V, Suárez Fernández C, Freire Castro SJ, Luordo D, Pesqueira Fontan PM, Blázquez Encinar JC, Magallanes Gamboa JO, de la Peña Fernández A, Torres Peña JD, Fernández Solà J, Napal Lecumberri JJ, Amorós Martínez F, Guisado Espartero ME, Jorge Ripper C, Gómez Méndez R, Vicente López N, Román Bernal B, Rojano Rivero MG, Ramos Rincón JM, Gómez Huelgas R; SEMI-COVID-19 Network. 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. Ann Med. 2021 Dec;53(1):103-116. doi: 10.1080/07853890.2020.1836566. PMID: 33063540; PMCID: PMC7651248.
3 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)
4 Watts DL: The nutritional relationship of zinc. /. Ortho. Med. 3,2, 1988.
5 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/ijms18102222PMCID: PMC5666901PMID: 29064429
6 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/nu9121286PMCID: PMC5748737PMID: 29186856https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748737/
7 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
8 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.2014.02.031http://www.sciencedirect.com/science/article/pii/S0197458014003595
9 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.S79121PMCID: PMC5245916PMID: 28144156
10 McQuaid A, Lamand M, Mason J. The interactions of penicillamine with copper in vivo and the effect on hepatic metallothionein levels and copper/zinc distribution: the implications for Wilson's disease and arthritis therapy. J Lab Clin Med. 1992 Jun;119(6):744-50. PMID: 1593220.
11 Penicillamine Drug Information, Kaiser Washington https://wa.kaiserpermanente.org/kbase/topic.jhtml?docId=hn-1453000
12 Winchester Hospital Health Library. Penicillamine (Trade Names: Cuprimine, Depen)https://www.winchesterhospital.org/health-library/article?id=21631
13 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)
14 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/
15 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)
16 Zinc - Health Professional Fact Sheet - Office of Dietary Supplements - Table 2https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/
17 Barges, D.; JOREM. https://app.site123.com/about-jorem?w=3290035
18 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: PMC7580816PMID: 33094446https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580816/
19 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/nu12030762PMCID: PMC7146416PMID: 32183116https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146416/
20 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.
21 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
22 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
23 Linus Pauling Institute - Micronutrient Information Center - Minerals » Zinchttps://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 [27,28] included in demographics; zinc reducing rate of diabetes - as copper antagonist?)
24 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
25 MTHFR methylenetetrahydrofolate reductase [ Homo sapiens (human) ]; Gene ID: 4524, updated on 29-Nov-2020https://www.ncbi.nlm.nih.gov/gene/4524
26 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/s41398-018-0276-6PMCID: PMC6218441PMID: 30397195
27 The Walsh Institute - Biochemical Individualityhttps://www.walshinstitute.org/biochemical-individuality--nutrition.htmlCovered by inurance; one example;https://askdrgil.com/frequently-asked-questions/
28 Maxfield L, Crane JS. Zinc deficiency. 2020, StatPearls Publishing LLC.
29 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
30 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
31 Hanin Ghrayeb, Mazen Elias, Jeries Nashashibi, Awni Youssef, Mari Manal, Liala Mahagna, Masalha Refaat, Naama Schwartz, Adi Elias, Emanuele Bobbio. 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.0234209PMCID: PMC7272047PMID: 32497136https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272047/#:~:text=Iron%20deficiency%20anemia%20(IDA)%20is,the%20major%20regulators%20of%20appetite.
32 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
33 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
34 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.PrasadPMCID: PMC2277319PMID: 18385818https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2277319
35 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/
36 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.
37 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.
38 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-2017-000668corr1PMCID: PMC5888441PMID: 29634047https://pubmed.ncbi.nlm.nih.gov/29387426/
39 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: 679127PMCID: PMC1818130https://pubmed.ncbi.nlm.nih.gov/679127/
40 Lipinski B, Lipinska I. Effect of magnesium on fibrin formation from lower molecular weight (LMW) fibrinogen. Magnes Res. 2000;13(4):233-237.PMID: 11153893https://pubmed.ncbi.nlm.nih.gov/11153893/
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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/).
