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Mani’s metabolic musings

Garlic, sugar & COVID19 11-13.7.2020| Sugar & infection | Aged garlic | Tight Glucose control | Sugars & protein function | Sugars & nerve sheaths | Virality or vitality? |Glycan shield or glucose sword | Sugar coated stealth | Chronic vs acute immune response| Colds, coronavirus and COVID-19 | Internal or external terrain? 15.7.2020| Hygiene hypothesis & innate immunity references |

This page is a collection of cherry-picked articles from Twitter, Reddit, Facebook, Instagram, LinkedIn and other social media or news sites that I come across relating to metabolism. It’s not a curated or developed stream of ideas, just thought-provoking concepts or perhaps more aptly, thoughts that add to confirm my biases that metabolic health is a topic that we should all pay attention to.

11.7.2020 — Garlic, sugar & COVID19

I keep reading about the tight homeostatic control of blood glucose our bodies maintain, as well as the modification of proteins by glucose (glycation). From what I know, insulin, hemoglobin, albumin are all glycated to some degree or another. Glycated insulin does not work as effectively as normal insulin and in fact it appears to have many deleterious effects. Hemoglobin and myoglobin are likewise impaired and modified by glycation.

Attachment of sugar and infection to hemoglobin

It’s fun to muck about in the protein data bank looking for protein and sugar interactions. Here’s a summary depiction of an infected hemoglobin protein sequence with sugars attached (what do you think the person’s HbA1C was?) [Here’s the Protein Data Base sequence for glycated hemoglobin (3B75) — the fluorescent green circles indicate glycosylation sites. The purple squares are infection sites.]

Glycated human haemoglobin (hemoglobin) and infection sites
Glycated human haemoglobin (hemoglobin) and infection sites

The excessive cleavage of glucose, especially with important protein amino groups, can affect cell function and structure and create an inbalance (sic) which leads to cell destabilization. This condition seems to target organs and tissues that are not dependent on insulin for their absorption of glucose. Kidneys, blood vessels, peripheral nerves and lenses of the eye are more susceptible to damage from periods of hyperglycemia than other organs due to their lack of insulin dependence.

Dr Brian P Jakes. (2004 July 2). Glycosylation: What is it, how it affects patients with diabetes. Diabetes in Control. accessed (2020 July 13)

Here’s a 12 June 2020 article on glycated red blood cells (erythrocytes): Turpin C, Catan A, Guerin-Dubourg A, Debussche X, Bravo SB, Álvarez E, et al. (2020) Enhanced oxidative stress and damage in glycated erythrocytes. PLoS ONE 15(7): e0235335.

Of note, the substitution of a histidine for glycine residue can lead to conformational changes that result in sickle-cell anemia! Park, S. Y., Yokoyama, T., Shibayama, N., Shiro, Y., & Tame, J. R. (2006). 1.25 A resolution crystal structures of human haemoglobin in the oxy, deoxy and carbonmonoxy forms. J Mol Biol, 360(3), 690-701.

Aged garlic (S-allyl cysteine) seems to help, but dumping the Coke (sugar) works best?

We’re all looking for that magic pill to allow us to avoid swerving off our narrow tracks. Will cumin, green tea, black pepper, cinnamon block the effects of our dietary rampages? There’s information out there that says they might help. This link suggests that aged garlic (S-allyl cysteine) is a good antioxidant. —Colín-González, A. L., et al. (2012). The Antioxidant Mechanisms Underlying the Aged Garlic Extract- and S-Allylcysteine-Induced Protection. Oxidative medicine and cellular longevity. [n.b. Colín-González uses AGE for aged garlic extract, in my opinion a poor choice, since AGE is typically used to abbreviate advanced glycation end products.)

Mani's metabolic musings. Colín-González, A. L., et al. (2012). The Antioxidant Mechanisms Underlying the Aged Garlic Extract- and S-Allylcysteine-Induced Protection. Figure 2.
Antioxidant mechanism associated to S-allylcysteine (SAC).

Ahmad, M. S., Pischetsrieder, M., & Ahmed, N. (2007). Aged garlic extract and S-allyl cysteine prevent formation of advanced glycation endproducts. Eur J Pharmacol, 561(1-3), 32-38.

Where do I get aged garlic?

I sometimes take the slow path to making aged garlic (3 weeks) by fermentation in raw apple cider vinegar. How To Make Aged Garlic: The Benefits Of Garlic Without The Odor! The Natural Man. The fast method (10 days) uses a garlic fermenter (Black Garlic Fermenter) that automatically cycles the bulbs through heat cycles until a tasty treat emerges—there is no garlic smell, just a sweet umami flavor! Lastly, you can purchase aged garlic extract from commercial sources (it takes 20 months for them to make it!)

Viral infections are less virulent under tight glucose control?

“Improved glycemic control may improve outcomes in patients with novel coronavirus disease 2019 (COVID-19) and hyperglycemia, according to study results published in Diabetes Care.

“Patients with COVID-19 may present with stress hyperglycemia, which can cause overproduction of inflammatory cytokines and exacerbate disease progression. To determine whether tight glycemic control is warranted in patients with COVID-19 with moderate disease, investigators evaluated the effects of hyperglycemia on disease markers and outcomes in patients with COVID-19.” — Morgan E Meissner. (3.6.2020) Regardless of diabetes status, tight glucose control reduces risk for severe disease in COVID-19. Endocrinology Advisor.

Why do attached sugars impede protein function?

“Glycation is a major cause of spontaneous damage to proteins in physiological systems. This is exacerbated in diabetes as a consequence of the increase in glucose and other saccharides derivatives in plasma and at the sites of vascular complications.

Protein damage by the formation of early glycation adducts is limited to lysine side chain and N-terminal amino groups whereas later stage adducts, advanced glycation endproducts (AGEs), modify these and also arginine and cysteine residues. (recall the S-allylcysteine in aged garlic and the fact the cysteine is an important protein ligand by forming disulfide bonds.)

Metabolic dysfunction in vascular cells leads to the increased formation of methylglyoxal which adds disproportionately to the glycation damage in hyperglycaemia.” —Ahmed, N., & Thornalley, P. J. (2007). Advanced glycation endproducts: what is their relevance to diabetic complications? Diabetes Obes Metab, 9(3), 233-245.

Shapiro, R., McManus, M. J., Zalut, C., & Bunn, H. F. (1980). Sites of nonenzymatic glycosylation of human hemoglobin A. Journal of Biological Chemistry, 255(7), 3120-3127.

Sensi, M., Pricci, F., Andreani, D., & Di Mario, U. (1991). Advanced nonenzymatic glycation endproducts (AGE): their relevance to aging and the pathogenesis of late diabetic complications. Diabetes Res, 16(1), 1-9.

How does excess sugar affect nerve sheaths?

“The amount of nonenzymatic glycosylation present in normal and diabetic rat peripheral nerve myelin, whole brain, brain myelin, and individual myelin protein components was determined … Diabetic peripheral nerve myelin (PNS-M) showed a 5.2-fold increase over normal, indicating that myelin is the major peripheral nerve component undergoing excessive glycosylation in diabetes. SDS-PAGE of diabetic and normal PNS-M showed no differences in the pattern of protein bands or in the distribution of glycosylated adducts.

However, in the diabetic, the amount of incorporated radioactivity was 3.74 times greater in the P0 protein and 2.8 times greater in the high-molecular-weight material that did not enter the gel. In whole brain, a 2.4-fold increase in the amount of nonenzymatic glycosylation was observed when diabetic was compared with normal, while diabetic brain myelin (CNS-M) was 3.8 times more glycosylated than normal brain myelin. SDS-PAGE of diabetic and normal CNS-M, like that of PNS-M, showed no differences in the pattern of protein bands or in the distribution of glycosylated adducts.

The amount of incorporated radioactivity, however, was 3.18 times greater in the proteolipid region, 2.37 times greater for basic myelin protein, and 2.9 times greater for the high-molecular-weight proteins that did not enter the gel. This excessive nonenzymatic glycosylation of the main peripheral and central nervous system myelin components may contribute to the functional abnormalities of myelinated neurons associated with diabetes.” — Vlassara, H., Brownlee, M., & Cerami, A. (1983). Excessive nonenzymatic glycosylation of peripheral and central nervous system myelin components in diabetic rats. Diabetes, 32(7), 670-674.

Virality or vitality?

Louis Pasteur’s external terrain or Claude Bernard’s internal terrain.

Myelin-associated glycoprotein — a glycan shield turns into a glucose sword?

Viruses can form a coat of glucose (glycan shield) to protect themselves and allow entry through our immune system. Casalino, L., et al. (2020). Shielding and Beyond: The Roles of Glycans in SARS-CoV-2 Spike Protein. bioRxiv. Is the difference obvious is image?

COVID19 without and with a glycan shield
COVID19 without and with a glycan shield

The Protein Data Base (PDB) molecule of the month is hosted by David Goodsell who features interpretative drawings in his beautiful and informative books!

The major histocompatability complex (MHC) attacking myelin protein.

“Autoimmune Unwrapping — A combination of genetic and environmental problems can cause the immune system to attack one or more myelin proteins, leading to the destruction of the myelin sheath and causing the disease multiple sclerosis. The two structures shown here capture events in this terrible process. PDB entry 1pkq shows an antibody bound to MOG, which disrupts its function on the outer surface of the sheath. PDB entry 1bx2 shows a peptide from MBP being displayed by MHC, which will lead to mobilization of the immune system against MBP. PDB entry 1h15 (not shown) is complex of MHC with a similar viral peptide, showing how a viral infection can lead to immune responses that then cross react with normal proteins such as MBP.” David Goodsell. (2020 July). Myelin-associated GlycoproteinNerve axons are insulated and protected by a sheath of myelin. Protein Data Bank Educational Portal (PDB-101). Accessed 2020 July 11.

Sugar coated for stealth?

“If a catastrophe is an event which causes the loss of most expected value, a eucatastrophe is an event which causes there to be much more expected value after the event than before.”—The Foresight Institute. Where are you placing you bets: internal or external terrain?

Creon Levit’s explanation is filled with gorgeous imagery and deep insights that you should not only watch for the information on viruses, but for the love of life it explores every second of the presentation. Immunology Deep Dive: Creon Levit| Planet Labs Foresight Institute Creon Levit, Planet Labs Zoom.

“And by the way, if you have cytokines all the time in your diet, because you’re eating sugar, and you’re eating seed oils, and you have pollution and all this kind of stuff, then the cytokines are going to always be putting yourselves in an antiviral state, which paradoxically is going to weaken them against viruses. As you might imagine, if you chronically excite a system that’s only supposed to be excited, once in a while, when you’re acutely infected, you end up kind of burning it out and just screwing everything up by having your cells in an inefficient state all the time instead of specially turned on to a special state only when they’re infected by viruses. So, this is part of not the cytokine storm, but the degradation of the general metabolic system that comes about from chronic cytokine release.”

Creon Levit — Immunology Deep Dive.

Chronic and acute immune responses matter?

Creon’s insight that creating a permanent state of inflammation impairs immune system response has been known for quite some time. Take interferon (IFN), cytokines that stimulates immune system response, interactions. They can either help control viral and bacterial infections or “lead to immunosuppression and loss of virus control during chronic viral infections.” They’re like an army that’s often called to quell civil disturbances, before too long they become a mob attacking citizens. —McNab, F., Mayer-Barber, K., Sher, A., Wack, A., & O’Garra, A. (2015). Type I interferons in infectious disease. Nature Reviews Immunology, 15(2), 87-103. And here’s a 10 July 2020 paper: Lee, J. S., et al. (2020). Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Science Immunology, 5(49), eabd1554.

Internal or external terrain—which one are you cultivating?

Colds, coronavirus and COVID-19

Levit also tweeted: “(creon levit@creon·) “…Here is that rarest of documents: a *peer-reviewed* paper from top labs published in a top journal. Showing that the common cold probably confers some immunity to CV-19.” Skim this paper, it will give you insight is why the majority of individuals are asymptomatic. — Grifoni, A., et al. (2020). Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell.

SARS-CoV-2 (COVID19) Spike

The spike protein is composed of three identical chains, that together form a complex with a small domain inside the virus, a membrane-spanning segment, and a large ectodomain that extends outward from the virus. In addition, the spike is a glycoprotein: the ectodomain is covered with sugar chains that help to mask the virus from the immune system. … Both of these structures include only portions of the many sugar chains that coat the spike, since the sugars are highly flexible and difficult to observe.

David Goodsell. SARS-CoV-2 Spike. (2020 June) Molecule of the Month. Protein Data Base. doi:10.2210/rcsb_pdb/mom_2020_6

Internal or external terrain?

Internal or external terrain? Sanitized bubble or hands in the dirt? —Modern sanitation’s quandary (hygiene hypothesis)

“One of the main terrain-theory scientists was Antoine Béchamp (1816-1908). Pasteur and Béchamp were bitter rivals over several scientific issues. The book Pasteur: Plagiarist, Imposter (R. B. Pearson, 1942) even suggests that Pasteur plagiarized some of his work from Béchamp—no doubt a sore point with the latter, who ultimately died in obscurity. Pasteur, by contrast, became a skilled self-promoter who literally managed to make himself a household name long past the time of his death.”

“The other main proponent of the terrain theory was Claude Bernard (1813-1878), who (notwithstanding their differences of opinion on scientific issues) was a close friend and associate of Pasteur’s. At the end of his life, Pasteur is said to have recognized the importance of what Bernard had been trying to tell him, remarking, “Bernard avait raison. Le germ n’est rien, c’est le terrain qui est tout.” (Bernard was right. The germ is nothing, it’s the soil that is everything.)”

“In 1982, French scholar Marie Nonclercq published her doctoral thesis on Béchamp, alleging that Pasteur was not only a plagiarist but also a fraud and falsifier of experimental data. But regardless of Pasteur’s character, and regardless of whether he recanted at the end or not, what lives on after him is the mindset, clearly visible amongst most of today’s medical professionals and health care bureaucrats.”

“That it is, that the germ (formally designated SARS-CoV-2) that has to be tracked down, isolated, avoided, and eradicated – and that’s all that matters. The “terrain”, to conventional modern thinkers, is nothing.” —Selick, K. (2020). Selick: Coronavirus crisis reopens 150-year-old controversy. Western Standard. (added emphasis)…/selick-coronavirus…/

28.9.2020 Is diabetes a chronic state of perpetual preparation for hibernation?

Sepsis remains one of the leading causes of death in intensive care units. — Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death.

Schmoch, T.,et al. (2017). The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology. Int J Mol Sci, 18(3).

Metabolic dysfunction in sepsis and diabetes?

The concomitant profound metabolic changes are characterized by hyperglycemia, insulin resistance, and profound transformations of the intracellular energy supply in both peripheral and immune cells.

(Schmoch 2017)(Added emphasis)

When might insulin levels be high?

Insulin, the master anabolic hormone, at elevated levels (with some insulin resistance) when growing a baby, during an adolescent growth-spurt or when preparing for hibernation is healthy. In ancient times, a fast and feast cycle attuned to the seasons and food availability likely prevented modernity’s rampant obesity and diabetes epidemic. However, the inflammatory state induced by obesity and diabetes creates an internal terrain susceptible to infection that can lead to sepsis.

Sepsis and diabetes are multi-organ and pleiotropic?

Sepsis-associated mitochondrial dysfunction is multifactorial … — In solid organs such as kidney, liver, and heart taken from patients who died of protracted sepsis and in animal models, impaired mitochondrial function was seen alongside hydropic changes in mitochondria and mitophagy, yet cell death was minimal.

Shankar-Hari, M. & Singer, M. (2018) Sepsis, in Cavaillon, J.M. & Singer, M., eds., Inflammation: From molecular and cellular mechanisms to the clinic, vol 3, p. 1037

Sepsis and diabetes are hibernation physiology?

This has led to the hypothesis that mechanisms of organ dysfunction share similarities with hibernation physiology where cellular turnover is low and that organ dysfunction may even represent a late-stage adaptive process to a prolonged and severe insult.

(Shankar-Hari 2018)(Added emphasis)

Hygiene hypothesis and innate immunity references:

Bach, J.-F., & Chatenoud, L. (2012). The Hygiene Hypothesis: An Explanation For The Increased Frequency Of Insulin-Dependent Diabetes. Cold Spring Harbor perspectives in medicine, 2(2), a007799-a007799.

Kondrashova, A., Seiskari, T., Ilonen, J., Knip, M., & Hyoty, H. (2013). The ‘Hygiene hypothesis’ and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. Apmis, 121(6), 478-493.

Grifoni, A., et al. (2020). Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell.

Wrammert, J., et al. (2011). Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med, 208(1), 181-193.

Sekine, T., et al., Aleman, S., & Buggert, M. (2020). Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19. bioRxiv, 2020.2006.2029.174888.

Other articles and musings by Mani Malagon

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