Magnesium is an extremely important mineral needed to maintain cellular function. Its deficiency is associated with various diseases such as cancer, obesity, type 2 diabetes and neurological diseases. According to estimates, 537 million people are currently living with diabetes all over the world, and the numbers are increasing, with projections at 783 million by 2045.  The onset of insulin resistant (type 2) diabetes is preceded by metabolic syndrome, which is directly related to chronic magnesium deficiency. ¹

It cannot be overstated how important magnesium is to aerobic metabolism, protein synthesis, detoxification, immune function, bones and cardiovascular health. Studies have revealed that magnesium is used in at least 600 enzymatic functions, so it is by far the master mineral with the most jobs to do.  Furthermore, intracellular magnesium plays a role as a second messenger in the immune system, and has been recognized as a multi-target metabolic regulator.  Immune function, gut health and mitochondrial metabolism all depend on the availability of magnesium.

With the depletion of magnesium from soils and processed foods, combined with the excessive loss of magnesium via stress, it’s no wonder that degenerative disease via metabolic dysfunction is increasing globally.

Energy production depends on magnesium

Adenosine triphosphate (ATP), produced in the mitochondria, is the universal energy currency of cells and binds to the magnesium ion to become a biologically active form, contributing to energy metabolism. It is most often complexed as Mg-ATP and stored like a battery pack in the cell membrane.

Researchers have discovered that when magnesium is in short supply, the mitochondria also reduce production of ATP.  It was observed that when they blocked magnesium access, ATP production declined. “The mitochondrial Mg²⁺ channel MRS2 provides access for Mg²⁺ influx into mitochondria. Rats with functional inactivation of mutated MRS2 have major mitochondrial deficits with a reduction in ATP.^.  Therefore, uptake into mitochondria via MRS2 is essential for the maintenance of respiratory chain and cell viability.” ²

Low oxygen, low pH slows down metabolism and production of ATP

Researchers have observed that the pH of cells greatly influences metabolism, and that if pH becomes acidic, it results in sluggish clearance of waste products and free radicals, which hinders metabolism. Because low pH inhibits oxygen and leads to hypoxia, only anaerobic metabolism is left to produce energy. Anaerobic (without oxygen) metabolism is sugar metabolism, which makes only two ATP of energy per glucose molecule. This is 18 times less efficient than aerobic respiration (metabolism) using oxygen and magnesium in the mitochondria, which results in 36 ATP of electrical energy.

Ideal cell plasma pH is around 7.35, which can receive the oxygen saturation required for aerobic metabolism and optimal energy production.

Lactic acidosis – the over-balance of redox

REDOX is a type of chemical reaction involving change in pH via gain or loss of electrons. OXidation is the loss of electrons or an increase in the oxidation state, while REDuction is the gain of electrons or a decrease in the oxidation state. Think of electrons as giving power to build and maintain healthy life force. Acid wastes (oxidized materials and free radicals) have a deficit of electrons and steal the electrons from the neighboring good tissue cells.  Less electrons cause tissue breakdown, corruption and deterioration.

Regardless of whether anaerobic or aerobic, glycolysis produces acid if lactate is the end product of the pathway. The acid produced by glycolysis lowers the pH both inside cells where lactate is produced, as well as outside where protons can diffuse. Since the pH range in which cells can function is quite narrow (pH 7.0–7.6), uncontrolled glycolysis can lead to cell death. We need the body to be able to neutralize the acids to restore pH balance. If something goes wrong with that system, disease sets in.

Conditions that greatly increase anaerobic glycolysis are; low pH (acidosis), a shortage of oxygen (hypoxia) and magnesium deficiency. The consequence of the production of more acid than can be handled by the body’s buffering systems, is lactic acidosis – a life-threatening condition.  It can be dealt with most effectively by re-establishing the supply of oxygen, bicarbonate buffers, and the support of magnesium. Problems with metabolism, such as chronic fatigue and excessive weight gain, should be investigated and treated early with diet and lifestyle changes, so as to avoid further deterioration potentially into diabetes type 2.

Insulin sensitivity is a symptom of magnesium deficiency

The effect of cellular acidosis on all systems in the body can be devastating to health, because it leads to the resistance of insulin in metabolic syndromes like diabetes.  As magnesium is essential in protein synthesis in the body, magnesium’s depletion can adversely affect hormones, enzyme activity, collagen in skin, vessels and bones, and DNA function.

Insulin and magnesium synergistically support each other. As protein synthesis relies on magnesium (and is adversely affected by acidic environments), the production of pH-buffering or cell signaling enzymes, as well as production of insulin which supports access of magnesium to cells, all rely on availability of magnesium. It is a circular relationship and potentially a Catch-22 scenario as magnesium levels drop. Magnesium is also an electron donor working as an antioxidant, which influences pH balance.

Mitochondria are not only sensitive to free radical damage, but contribute to it as part of cell respiration. According to a 2021 review, “Mitochondria are known to generate approximately 90% of cellular reactive oxygen species (ROS). The imbalance between mitochondrial reactive oxygen species (mtROS) production and removal due to overproduction of ROS and/or decreased antioxidants defense activity results in oxidative stress (OS), which leads to oxidative damage that affects several cellular components such as lipids, DNA, and proteins. Since the kidney is a highly energetic organ, it is more vulnerable to damage caused by OS and thus its contribution to the development and progression of chronic kidney disease (CKD).”⁶

If not enough of the oxidative wastes are cleared and buffered, the mitochondria signal for the cell membrane channels to become more resistant to insulin and glucose (more the glucose than the insulin). If there is not enough oxygen and pH buffering capacity, cell membranes reduce the number of insulin receptors so as to prevent more fuel entering the cell. By inhibiting or reducing the entry of glucose, the mitochondria are thereby protected from further oxidative damage resulting from energy metabolism.  Excessive reactive oxygen species (ROS) free radicals can kill mitochondria unless they are neutralised.

It should be noted that blood plasma pH can be held in the normal range, whilst tissue cell plasma can drop in pH. In other words, blood tests for pH cannot necessarily tell you what the pH of tissue cells would be.  Low pH in tissue cells (eg. muscles) depresses metabolism. Loss of insulin sensitivity has been found in research to be directly related to cellular acidosis, which is associated with magnesium deficiency.

“We can consider acidosis as the constant pressure on the body’s physiology to compensate for all the acid-inducing challenges. Equally important, although the blood pH does not change, the pH in the cells and intracellular space becomes more acidic, causing disruption of enzyme function, loss of insulin sensitivity, and cellular metabolic adaptations.” ⁷

Excess lactate should get shuttled to the liver to undergo gluconeogenesis (ie. conversion to glucose). In the liver, magnesium is an important regulator of enzymes in gluconeogenesis. ⁵ However, if the liver is overloaded and magnesium deficiency with lower pH prevails, the whole system can become sluggish, with a slower waste clearance and a diminishing pH buffering capacity. The slower the detoxification and clearance, the more the acidosis grows. Therefore, pathologic and persistent lactic acidosis occurs when there is excessive production of lactate which exceeds the liver’s capacity to metabolize it. ⁸

In addition, as cell membranes become resistant to insulin and glucose, more is released into the blood. This excess insulin and glucose then has to be cleared by the liver. The liver is therefore under a lot of pressure and stores the unused energy as fat cells, which can also contain free radicals from the uncleared wastes.  If there are insufficient antioxidants available as electron donors, lipids (as cholesterol) can become corrupted and oxidised. This leads to dyslipidaemia and eventually cardiovascular disease.

Researchers have found that those with cellular magnesium depletion have a higher risk of developing lactic acidosis. “Magnesium deficiency is a common finding in patients admitted to the ICU and is associated with lactic acidosis. Our findings support the biologic role of magnesium in metabolism and raise the possibility that hypomagnesemia is a correctable risk factor for lactic acidosis in critical illness.” ⁹

The 2019 Kostov study regarding chronic systemic inflammation concluded that magnesium deficiency triggers both systemic inflammation and insulin resistance: “Mg²⁺ regulates electrical activity and insulin secretion in pancreatic beta-cells. Intracellular Mg²⁺ concentrations are critical for the phosphorylation of the insulin receptor and other downstream signal kinases of the target cells. Low Mg²⁺ levels result in a defective tyrosine kinase activity, post-receptor impairment in insulin action, altered cellular glucose transport, and decreased cellular glucose utilization, which promotes peripheral insulin resistence in Type 2 Diabetes. Magnesium deficiency triggers chronic systemic inflammation that also potentiates insulin resistence. People with Type 2 Diabetes may end up in a vicious circle in which magnesium deficiency increases insulin resistence and insulin resistence causes magnesium deficiency, that requires periodic monitoring of serum Mg²⁺ levels.” ⁵

So the more inflammation in the body, the more we lose magnesium and the worse the magnesium deficiency becomes; and the lower the magnesium, the more inflammation and insulin resistance results. This then inhibits magnesium entry to cells because magnesium enters via insulin receptors. It becomes a negative feedback loop, like a Catch-22 situation or revolving door with no escape opening.

The reason chronic inflammation and pain cause excessive loss of magnesium is because they are significant stressors. Stress increases acid byproducts, leading eventually to anaerobic glycolysis (sugar metabolism) which in turn increases acidosis, triggers kidneys to excrete more magnesium via urine.

Eventually the kidney tubules can become stiffer and weaker due to calcium deposition – a direct result of chronic acidosis. This affects the kidneys’ ability to recycle enough magnesium, and more keeps getting lost in the urine (along with other alkali minerals), which means it becomes increasingly difficult to stabilise pH in cells.

Hormone signalling enhances magnesium uptake in cells

It’s also interesting to note that supplementation of insulin supports the recovery of magnesium and ATP, which was demonstrated in a study of cardiac cells in rats. “Treatment of diabetic animals with exogenous insulin for 2 weeks restored ATP and protein levels as well as Mg(2+) homeostasis and transport to levels comparable to those observed in non-diabetic animals.” ¹⁰

A review on the role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X found: “In vitro and in vivo studies have demonstrated that insulin may modulate the shift of Mg from extracellular to intracellular space.” This is an important observation because if insulin can assist entry of magnesium to cells, this would also help to restore cell pH, mitochondrial function and Mg-ATP levels. They went on to say that epidemiological studies show that high daily magnesium intake are predictive of a lower incidence of Non-Insulin Dependent Diabetes Mellitus (Type2D). ¹¹   Insulin has therefore been shown to be a magnesium-conserving hormone.

Cancer cells love anaerobic glycolysis

The negative feedback loop of acidosis, inflammation and magnesium deficiency is exacerbated by cancer cells because they have an exceptionally high capacity for glycolysis (anaerobic sugar metabolism). Even when oxygen is available, cancer cells produce much of their ATP by anaerobic glycolysis, and thereby produce more acids.

The ability to produce sufficient ATP by a pathway that does not require oxygen gives cancer cells a selective advantage over normal cells. ⁴  This is a big topic for another article, but should be mentioned as part of the overview of deleterious effects of acidosis in metabolic syndromes.

How to supplement with more magnesium

The best way to know if you need more magnesium is to be guided by the symptoms.  If acidosis persists, we can be fairly sure it is connected to magnesium deficiency. However, there are also a constellation of other symptoms that can indicate magnesium deficiency, such as anxiety, sleep problems, cramps and involuntary muscle movements (like restless legs), digestion problems, skin disorders, chronic inflammation, depression of energy, mental fog, obesity, osteoporosis and other bone disorders, hypertension, heart arrhythmia, arthritis, immune disorders (including cancer) – and the list goes on.

Just as the blood pH is not an accurate indicator of tissue cell pH, the same goes for magnesium levels in the blood not being an accurate indicator of tissue cell magnesium stores. Only 1% of the total magnesium in the body is present in extracellular fluids and only 0.3% is found in the blood serum. Tissue cells are known to sacrifice their stored magnesium in order to keep the free magnesium ions in the blood within the normal range. By the time hypomagnesemia shows up via blood tests, the tissue cells would have become more significantly depleted.

A number of factors can negatively affect magnesium balance in the body and, in the long-term, may result in magnesium deficiency. Such factors may be a decreased intake of magnesium from the food or drinking water, an increased magnesium loss through the kidneys, an impaired intestinal absorption of magnesium, as well as prolonged use of some medications causing hypomagnesemia.

Once magnesium deficiency symptoms present, we need a lot more magnesium supplementation than what is recommended as a ‘maintenance dose’ for young people.  As we age we also tend to store less magnesium in cells, thereby becoming more prone to oxidative stress.  It is common for people with magnesium deficiency symptoms to need as much as 1,000mg a day to help regulate and maintain magnesium homeostasis. Supplementation with insulin and other magnesium supporting vitamins like B6 can also be helpful.

Extra magnesium can be taken up via an organic diet, including bone broth which is rich in minerals, as well as magnesium drinking water that mimics natural spring waters. In drinking water, the levels of magnesium should be ideally 25–100 mg/L. ⁵    However, in high-end magnesium deficiency cases the digestive system and gut health tends to be so compromised that it is not possible to get enough magnesium via diet alone.

Transdermal magnesium using magnesium chloride in solution, which offers the highest bioavailability, offers fast and efficient uptake of magnesium without burdening the digestive system, and can supply the extra magnesium needed. Apart from an intravenous magnesium infusion, transdermal magnesium offers the best opportunity for high magnesium uptake and can be easily incorporated into daily lifestyle habits.

This can be done via magnesium bathing and/or using daily magnesium cream, oil and lotion. There are no contraindications and the body self-regulates the magnesium it takes up from skin, so there is no risk of overdose. Note that plant oils and extracts within Elektra Magnesium products enhance epidermal magnesium absorption, and there are no toxic chemical ingredients. They also provide extra benefits in skin care, anti-ageing, relaxing muscle massage and promotion of better sleep quality. A Magnesium Dose Guide for these transdermal products is available at: https://www.elektramagnesium.com.au/faq/
Professionals’ Review: https://youtu.be/qoB4PZhdfJ4

By Sandy Sanderson (B.A. Uni NSW / CEO of Elektra Life Pty Ltd)
© 2023   www.elektramagnesium.com.au

REFERENCES:

(1)   Mildred S. Seelig. Magnesium Deficiency in the Pathogenesis of Disease; Springer US, 1980.

(2)   Yamanaka, R.; Tabata, S.; Shindo, Y.; Hotta, K.; Suzuki, K.; Soga, T.; Oka, K. Mitochondrial Mg2+ Homeostasis Decides Cellular Energy Metabolism and Vulnerability to Stress. Sci Rep 2016, 6, 30027. https://doi.org/10.1038/srep30027.

(3)   Merolle, L.; Sponder, G.; Sargenti, A.; Mastrototaro, L.; Cappadone, C.; Farruggia, G.; Procopio, A.; Malucelli, E.; Parisse, P.; Gianoncelli, A.; Aschenbach, J. R.; Kolisek, M.; Iotti, S. Overexpression of the Mitochondrial Mg Channel MRS2 Increases Total Cellular Mg Concentration and Influences Sensitivity to Apoptosis. Metallomics 2018, 10 (7), 917–928. https://doi.org/10.1039/c8mt00050f.

(4)   Harris, R. A. Glycolysis Overview. In Encyclopedia of Biological Chemistry (Second Edition); Lennarz, W. J., Lane, M. D., Eds.; Academic Press: Waltham, 2013; pp 443–447. https://doi.org/10.1016/B978-0-12-378630-2.00044-X.

(5)   Kostov, K. Effects of Magnesium Deficiency on Mechanisms of Insulin Resistance in Type 2 Diabetes: Focusing on the Processes of Insulin Secretion and Signaling. Int J Mol Sci 2019, 20 (6), 1351. https://doi.org/10.3390/ijms20061351.

(6)   Tirichen, H.; Yaigoub, H.; Xu, W.; Wu, C.; Li, R.; Li, Y. Mitochondrial Reactive Oxygen Species and Their Contribution in Chronic Kidney Disease Progression Through Oxidative Stress. Frontiers in Physiology 2021, 12.

(7)   Pizzorno, J. Acidosis: An Old Idea Validated by New Research. Integr Med (Encinitas) 2015, 14 (1), 8–12.

(8)   Foucher, C. D.; Tubben, R. E. Lactic Acidosis. In StatPearls; StatPearls Publishing: Treasure Island (FL), 2023.

(9)   Moskowitz, A.; Lee, J.; Donnino, M. W.; Mark, R.; Celi, L. A.; Danziger, J. The Association Between Admission Magnesium Concentrations and Lactic Acidosis in Critical Illness. J Intensive Care Med 2016, 31 (3), 187–192. https://doi.org/10.1177/0885066614530659.

(10) Reed, G.; Cefaratti, C.; Berti-Mattera, L. N.; Romani, A. Lack of Insulin Impairs Mg2+ Homeostasis and Transport in Cardiac Cells of Streptozotocin-Injected Diabetic Rats. J Cell Biochem 2008, 104 (3), 1034–1053. https://doi.org/10.1002/jcb.21690.

(11) Barbagallo, M.; Dominguez, L. J.; Galioto, A.; Ferlisi, A.; Cani, C.; Malfa, L.; Pineo, A.; Busardo’, A.; Paolisso, G. Role of Magnesium in Insulin Action, Diabetes and Cardio-Metabolic Syndrome X. Mol Aspects Med 2003, 24 (1–3), 39–52. https://doi.org/10.1016/s0098-2997(02)00090-0.

(12) Dai, L.-J.; Ritchie, G.; Bapty, B. W.; Kerstan, D.; Quamme, G. A. Insulin Stimulates Mg2+ Uptake in Mouse Distal Convoluted Tubule Cells. American Journal of Physiology-Renal Physiology 1999, 277 (6), F907–F913. https://doi.org/10.1152/ajprenal.1999.277.6.F907.