Insulin Resistance, Metabolic Syndrome, Diabetes and Magnesium Deficiency

As magnesium is such an important cation 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 metabolism, protein synthesis, detoxification, immune function, bones, cardiovascular health and brain function. 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. It has been recognized as a multi-target regulator of immune function, gut health and mitochondrial metabolism of ATP (adenosine triphosphate), our electrical energy currency.

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.

Magnesium is essential for mitochondrial energy metabolism

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. Magnesium is most often complexed and stored in cells as Mg-ATP. After energy discharge and release of the third phosphate, adenosine diphosphate (ADP) is left behind, but magnesium also participates in the recharging of ADP back to ATP.

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 magnesium channel MRS2 provides access for magnesium 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

In another study the powerful influence of magnesium in mitochondrial metabolism was demonstrated in reverse, via extra MRS2 channels which increased magnesium uptake: “We observed a remarkable increase of total intracellular magnesium concentration in cells overexpressing MRS2 compared with control cells… We found that cells overexpressing the MRS2 channel became less responsive to these pharmacological insults. Our experimental evidence indicates that the MRS2 channel controls overall intracellular magnesium levels, the alteration of which might have a role in the molecular signaling, leading to apoptotic cell death.” ³

Magnesium is needed for mitochondrial membrane ion channel regulation of the electrolytes calcium and potassium. Mitochondria represent an important intracellular magnesium storage vessel. They use magnesium to alter the voltage-dependent calcium and potassium ion channels that open and close as needed for electrolyte homeostasis. 

Low oxygen and low pH slow down energy metabolism 

Researchers have observed that the pH of cells greatly influences metabolism, and that if pH becomes acidic, it coincides with sluggish clearance of waste products which are free radicals that hinder mitochondrial metabolism. Metabolism itself causes waste byproducts, and if too many accumulate they can kill our mitochondria. However the cell has mechanisms to clean up wastes and rebalance, in order to protect mitochondria and our energy supply.

Cellular oxidative stress from toxicity and excessive Reactive Oxygen Species (ROS) pushes pH lower. A healthy body uses magnesium to make our most potent antioxidant enzymes - glutathione and superoxide dismutase - which can neutralise and detox the ROS, and thereby maintain cell pH stability. Magnesium is used to counteract oxidative stress and restore energy productivity.

In addition, low (acidic) pH inhibits oxygen saturation. As we need oxygen for energy metabolism, the hypoxic or low oxygen state inhibits the amount of energy that can be produced. Anaerobic glycolysis (sugar metabolism) is much less energy efficient, making only two ATP of energy per glucose molecule. This is 18 times less efficient than aerobic respiration. The equation for aerobic cellular respiration to make ATP is:

C₆H₁₂O₆ + 6O₂ à 6CO₂ + 6H₂O + ATP.

Therefore, aerobic glycolysis (metabolism) results in 36 ATP produced, whereas without the oxygen, the pathway produces only 2 ATP. 

Constant cravings, never satisfied, but low energy output

The lower the energy output, the more the body craves carbohydrates for a quick fix, so you keep looking for food, but satisfaction is only short term. More fuel goes in, but you can't use it. The body uses a lot more magnesium to burn carbohydrates (glycolysis) compared to fat burning (ketosis), so it can't use all that extra carbohydrate fuel if magnesium is low, oxygen is low and acidity is on the rise. The cell can't afford to risk damaging mitochondria with so much extra reving of its engine, when the engine is clogged with wastes.

This cascade of issues is associated in metabolic syndrome and insulin resistance, whereby the cell starts to inhibit entry of extra glucose into the cell in order to protect mitochondria from the extra oxidative stress produced by metabolism. The cell would rather have less energy than have it's mitochondria kick the bucket. In other words, getting overloaded with glucose from carbohydrates spikes insulin release to bring more glucose to the cell, but the doors close to more metabolic stimulation, which forces the liver to remove the excess blood sugar and insulin, and store it as plumped up distended fat cells in adipose tissue. Therefore hyperinsulinemia leads to insulin resistence, chronic fatigue and excessive weight gain.

Lactic acidosis – the over-balance of redox

Regardless of whether anaerobic or aerobic, glycolysis produces acid, as lactate is the end product of the metabolic pathway. The acid produced by glycolysis lowers 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 mitochondrial and cell death. Eventually this manifests as disease.

The balancing game to maintain healthy function works via REDOX - a type of chemical reaction involving change in pH via gain or loss of electrons. OXidation is the loss of electrons, that is an increase in the oxidation state, while REDuction is the gain of electrons or a decrease in the oxidation state. It's like a seesaw always trying to find balance.

Oxidated metabolic byproducts (oxidants) are 'used up' molecules in the metabolic process because they lost electrons in their outer valence shell, thereby having hungry gaps to fill, and thus making them free radicals or 'electron stealers' of other molecules they encounter. This is why they can become so destructive if not neutralised by antioxidant molecules (also called free radical scavengers). 

As we need more electrons for cell energy production, our body has to consume or make 'antioxidants' such as glutathione (GSH), a potent detoxification hormone containing sulfur, which can neutralise free radicals by satisfying their hunger and donating electrons. Electron donors and electron stealers attract each other like magnets. Magnesium is an antioxidant and is also necessary for the liver to make glutathione. Once the waste products are neutralised they are taken to the liver for disposal into the colon. stopping the chain reactions that damage cellular components like DNA, proteins, and lipids. This process mitigates oxidative stress and protects against chronic diseases.

Conditions that greatly increase anaerobic glycolysis because of a shortage of oxygen (hypoxia) include respiratory and blood circulation disorders. The consequence of the production of more acids and free radicals than can be handled by the body’s buffering systems, is called 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. "It is important to reinstate ATP synthesis via oxidative phosphorylation [oxygen metabolism], which will inhibit the production of lactic acid by glycolysis." It will, “promote the oxidation of lactate as well as the consumption of the excess acid (H+'s) by the sum reaction: 2Lactate−+2H++6O2→6CO2+6H2O.” 4

Insulin sensitivity

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. Insulin, as well as the detoxing antioxidant hormones of Glutathione and Superoxide Dismutase, are all proteins, which are adversely affected by the acidic environments of oxidative stress. The production of pH-buffering and cell signaling enzymes, as well as production of insulin which escorts magnesium's access to the cell, are all crucially dependent on the availability of magnesium.

Magnesium has to get in with the help of insulin, but the body can't make insulin without enough magnesium. Oxidative stress results from low magnesium, and the worse the oxidative stress, the more it depletes magnesium. It is a viscious negative feedback loop: As magnesium levels drop, oxidative stress increases free radicals like Reactive Oxygen Species (ROS), which overload the cell, as there are not enough antioxidant enzymes to help clean up the cell environment. 

We can absorb free radicals from oxidated and over-processed foods, but mitochondria contribute a lot more to free radical production as part of cell energy metabolism. 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. If there is not enough oxygen and pH buffering capacity, cell membranes close the doors to more fuel entering, in order to protect mitochondria form oxidative damage.

It should be noted that blood plasma pH can be held in the normal range, while tissue cell plasma can drop in pH, making blood pH not an indicator of tissue cell pH. Low pH in tissue cells, which house our mitochondria, depresses mitochondrial 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 prevails with lower pH levels, 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

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

Furthermore, as cell membranes become resistant to insulin and glucose, the excess that is building in the blood can damage the endothelial linings, contributing to cardiovascular disease and hardening of the arteries. This overload eventually triggers membrane insulin receptors to respond to the cell's stress signals by keeping the doors shut, and restricting entry to only minimal glucose. The excess insulin and blood sugar then has to be cleared by the liver in order to protect vessels, so it stores the unused energy in swollen fat cells via adipose tissue around the middle.

If there are insufficient antioxidants available as electron donors, lipids (as cholesterol) can become corrupted and oxidised, attracting and trapping free radicals. This leads to dyslipidaemia (corrupted cholesterol and excess LDL), resulting eventually in atherosclerosis.

Low magnesium triggers stress, inflammation and insulin resistance

The 2019 Kostov study regarding chronic systemic inflammation concluded that magnesium deficiency triggers both systemic inflammation and insulin resistance, but conversely, insulin resistance also deprives the cell of the valuable magnesium it needs for respiration:

“Magnesium 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 magnesium 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.” ⁵

The reason chronic inflammation and pain cause excessive loss of magnesium is because they are significant stressors. Stress, and its associated adrenalin release, increases glycolysis, which increases ROS waste products and acidosis, as well as dehydration. Cells need more magnesium for energy production, as well as cell detox, but if the kidneys lose too much magnesium or there is not enough new supply, acidosis is not resolved, and energy metabolism consequently slows down.

Eventually the kidney tubules can become stiffer due to calcium deposition – a direct result of chronic acidosis, as calcium is used by the body as an alkalising mineral when magnesium is in short supply. If the kidney tubules become stiffer It affects the insulin receptors of the kidneys and therefore their ability to recycle enough magnesium. So more keeps getting lost in the urine (along with other alkali minerals), which means it becomes increasingly difficult to stabilise pH in the REDOX function.

Insulin escorts magnesium to gain cell access

It's 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 magnesium 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 magnesium 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 (Type 2 Diabetes). ¹¹

Insulin has therefore been shown to be a magnesium-optimising hormone. Its effect to assist cellular magnesium homeostasis is shown in how the kidneys regulate magnesium electrolytes: “Insulin receptor binding is highest along the medullary thick ascending limb and distal convoluted tubule; so by inference insulin may affect electrolyte transport within these segments.” In other words, our kidneys try to conserve magnesium wherever possible via their extra insulin receptors.  Magnesium conservation is also diminished in hyperglycemic (excess blood glucose) and insulin-resistent diabetic states.

Remember that we need magnesium to make proteins in the first place, including our antioxidant hormones for neutralising free radicals, as well as hormones like insulin and parathyroid hormone which are important for metabolism and electrolyte balance.

The authors of the study also concluded that insulin and parathyroid hormone work even better in tandem to help magnesium gain entry to cells: “As insulin associates with many different hormone signaling pathways, including cAMP-dependent mediation, we measured cAMP formation and magnesium uptake in cells treated with both hormones. Parathyroid hormone and insulin increased cAMP levels and magnesium entry rates to a greater extent than each of the hormones alone. These data give credence to the notion that insulin potentiates parathyroid-stimulated magnesium uptake.” ¹² 

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 enzymatic capacity for glycolysis. Even when oxygen is available, cancer cells produce much of their ATP by anaerobic glycolysis. 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 and therefore a weaker antioxidant detox system. 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 , with only 0.3% found in the blood serum. Blood tests generally indicate the normal range between 1.8 and 2.6 mg/dL. Tissue cells in muscle and bone are known to sacrifice their stored magnesium in order to keep blood magnesium within the normal range. By the time hypomagnesemia shows up via blood tests, the tissue cells would have become significantly depleted.

A number of factors can negatively affect magnesium balance and homeostasis 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, excessive stress or trauma, 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 and chronic fatigue.

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 for those with hyperglycemia. But if insulin is oversupplied you can end up with hypoglycemia causing sudden energy crashes and dizziness. The balancing is the challenge.

To avoid the roller coaster of highs and lows in energy level, it is recommended to eat a low carbohydrate diet which minimises glucose, and therefore helps to conserve magnesium loss. 28 magnesium molecules are used to produce energy from a sucrose molecule, and 56 magnesium molecules are used for a fructose molecule.  Fructose is eventually converted to glucose, so it ends up in the same pathways doing the same things, but using up more magmnesium in the process.

Every time you eat carbohydrates you stimulate insulin release from the pancreas. Sugars and starches spike the blood insulin, eventually leading to hyperinsulinemia and inflammatory conditions. Lowering sugars, increasing dietary magnesium, increasing ketosis (fat burning) via smaller window of eating during the day (as well as exercise), starts to tip the scales back again to balance the pH of cells and protect the mitochondria, which enhances metabolism. 

Extra magnesium can be taken up via an organic meat based diet rich in minerals and animal fats, as well as magnesium drinking water that mimics natural spring waters. In drinking water, the levels of magnesium should be at least 25 and optimally closer to 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.  High supplement concentrations cause gut irritation, watery stool and quick elimination before the magnesium has a chance to be absorbed to the interior.

Transdermal magnesium using magnesium chloride in solution, in contrast, offers the highest bioavailability, with fast and efficient uptake of magnesium ions without burdening the digestive system, efficiently supplying 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 skin and body care products. 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 contain 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)
© 2023-2026 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.