Insulin Resistance, 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 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 of ATP (adenosine triphosphate), our electrical energy currency, 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.

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 participates in the formation of ATP and is most often complexed as Mg-ATP. After energy discharge, which releases the third phosphate and leaves behind adenosine diphosphate (ADP), 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 also regulates calcium and potassium homeostasis in mitochondria. Mitochondria represent an important intracellular magnesium store, which they use to alter the electrophysiological properties of ion channels such as voltage-dependent calcium and potassium channels. 

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 and free radicals, which hinder mitochondrial metabolism.  Excessive oxidative stress from toxicity pushes pH lower.

In addition, low (acidic) pH inhibits oxygen saturation, which we need for metabolism, leading to hypoxia (low or no oxygen). This state means that only anaerobic glucose metabolism (glycolysis) is able to produce energy, but it's 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. 

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 can't use all that extra carbohydrate fuel if magnesium is low, oxygen is low and acidity is on the rise, so the cell starts to inhibit entry of extra glucose into the cell in order to protect mitochondria from the extra oxidative stress of metabolism. The cell would rather have less energy than have it's mitochondria kick the bucket. In other words, getting overloaded with glucose causes insulin resistence and excessive weight gain.

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, that is an increase in the oxidation state, while REDuction is the gain of electrons or a decrease in the oxidation state. Oxidated metabolic byproducts (oxidants) are in a sense 'used up' because they lost electrons via metabolism, and now have hungry gaps to fill, making them free radical 'electron stealers' of other molecules they encounters. 

As we need more electrons for cell energy, our body has to consume or make 'antioxidants' such as glutathione (GSH), a detoxification hormone containing sulfur, which can neutralise the free radicals by donating electrons. Electron donors and electron stealers attract each other like magnets. Magnesium is also an electron donor and is necessary for the liver to make glutathione. Once the waste products are neutralised they are taken to the liver for disposal into the colon.

Regardless of whether anaerobic or aerobic, glycolysis produces acid, as lactate is the end product of the 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.

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 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. "It is important to reinstate ATP synthesis via oxidative phosphorylation, which will inhibit the production of lactic acid by glycolysis. It will also, “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 and cellular access rely on magnesium

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 negative feedback loop, as magnesium levels drop and oxidative stress increases free radicals like Reactive Oxygen Species (ROS). 

Mitochondria are not only sensitive to free radical damage, but contribute to it 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 resulting from further respiration. 

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 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

In addition, as cell membranes become resistant to insulin and glucose, more is released into the blood. This triggers a reduction in membrane insulin receptors because the cell wants to keep the doors shut to the glucose. This excess insulin and glucose in the blood then has to be cleared by the liver. The liver is therefore under a lot of pressure, having to store the unused energy as fat cells (adipose tissue around the waste) to clear it out of the blood as quickly as possible, as glucose is potentially damaging to the blood vessel's endothelial lining.

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

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

Low magnesium triggers 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 helps magnesium gain access to cells

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-conserving 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.

The authors 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 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 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 it can end up as hypoglycemia in a sudden energy crash and dizziness. 

To avoid the roller coaster of highs and lows in energy level, it is recommended to eat a low carbohydrate diet to minimise the glucose that stimulates more insulin release.  Lowering sugars, increasing ketosis (fat burning), and increasing magnesium starts to tip the scales back to balance with a more efficient metabolism.  Regular moderate exercise also helps to circulate more oxygen and boost energy output.

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)
© 2023-2026 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.