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October 08, 2010

Inflammation and Insulin Resistance – Is Magnesium The Solution?

Insulin In healthy people, the hormone, insulin triggers the uptake of glucose from the bloodstream into the body’s cells. Subsequently, the sugar is either stored, or used in the production of cellular energy. When the cells of our body (specifically, muscle, fat, and liver cells) no longer respond properly to this blood–sugar–lowering effect of insulin, the phenomenon is, quite logically, called insulin resistance. In aging and disease, insulin resistance tends to increase, often causing blood sugar levels to become chronically elevated.

Of course, insulin resistance is well–known to be the metabolic forerunner of diabetes – and in both insulin resistance and diabetes, we find that magnesium is sure to play a particularly important role.

Via several different mechanisms, magnesium is able to reduce inflammation and improve the efficiency of cellular energy production, ultimately facilitating the proper metabolism of glucose. In previous Integrated Supplements Blog articles, for example, we presented research linking a lack of magnesium with the development of systemic inflammation, which leads to the elevation of blood lipids (i.e., triglycerides and cholesterol), and subsequently, insulin resistance:

Inflammation, Blood Lipids, Insulin Resistance, and Magnesium

But, it’s important to remember that the role of magnesium in blood–sugar–control is of far more than just academic interest. It can’t be stressed enough that sub–optimal magnesium intake is one of the most prevalent nutritional shortcomings of our modern age – even among those who eat well and take supplements. This fact is likely to have practical real–world significance for the millions of Americans who either have, or are at risk for, diabetes, and who exhibit other manifestations of the metabolic syndrome (e.g., abdominal obesity, elevated triglycerides, elevated blood pressure, and a prothrombotic/proinflammatory blood chemistry).

Magnesium and Blood–Sugar Control

The amount of research which illustrates magnesium’s essential role in proper blood sugar control is truly overwhelming. The following studies are just a small sample:

Study Link – Oral Magnesium Supplementation Improves Insulin Sensitivity and Metabolic Control in Type 2 Diabetic Subjects. A randomized double–blind controlled trial

Study Link – Serum and intracellular magnesium deficiency in patients with metabolic syndrome – evidences for its relation to insulin resistance.

Study Link – Magnesium deficiency produces insulin resistance and increased thromboxane synthesis.

Study Link – Improved insulin response and action by chronic magnesium administration in aged NIDDM subjects.

Study Link – Dietary Magnesium Intake in Relation to Plasma Insulin Levels and Risk of Type 2 Diabetes in Women.

Study Link – Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium.

And it’s not just diabetics who should be concerned with their magnesium status, plasma magnesium concentrations have also been correlated with blood–sugar control in nondiabetics as well:

Study Link – Effect of Variations in Plasma Magnesium Concentration on Resistance to Insulin–Mediated Glucose Disposal in Nondiabetic Subjects.

Quote from the above study:

…when the 18 patients were analyzed together, there were significant ( P < 0.05 to P < 0.01) inverse correlations between Mg concentrations and glucose (r = –0.68) and insulin (r = –0.51) areas and [steady state plasma insulin and glucose] concentrations (r = –0.60). Thus, a low Mg concentration in nondiabetic subjects was associated with relative insulin resistance, glucose intolerance, and hyperinsulinemia.

But, regardless of how convincing the research is, in the eyes of the general public, magnesium’s role in insulin resistance and diabetes has yet to be recognized. In reading much of the popular literature on diabetes and insulin resistance, for example, we’d be led to believe that somehow, insulin receptors on the surface of the cell simply “wear out” as a result of a lifetime’s assault with dietary sugars and refined carbohydrates. But this sort of over–simplification can divert a person’s attention away from thinking about the deeper cellular processes which are truly important in controlling blood sugar. It can also blind a person to simple and effective strategies (including magnesium supplementation) which may be able to reverse the process.

In truth, we’ll only gain a meaningful insight into insulin resistance if we look beyond the “insulin receptor” on the surface of the cell, and towards the underlying energy–producing mechanisms inside the cell.

For example, it’s well–known that losing weight (i.e., losing body fat) invariably improves insulin resistance and diabetes. In fact, simply losing weight is often sufficient to completely abolish insulin resistance and diabetic symptoms. But how could this be if insulin receptors truly did “wear out?” This seemingly subtle semantic distinction is important, because, far too frequently, those diagnosed with type–2 diabetes are led to believe that they’ve been given something akin to a death sentence simply because they haven’t been fully informed of the underlying biological mechanisms at work.

If a useful understanding of diabetic metabolism is to be reached, the most important misconception to combat is that diabetes is merely a disorder of carbohydrate metabolism. In reality, when we look at how diabetes actually begins, it may be more fitting to classify diabetes as, fundamentally, a disorder of fat metabolism (including both the fat in our diet, and the fat we have stored in our body). In fact, we can only gain an understanding of glucose metabolism, insulin resistance, and mitochondrial dysfunction in diabetes when we first look at the chemical messages which are constantly being emitted by our body’s fat cells.

Despite another common misconception, our body fat isn’t simply a storehouse of inert energy – it’s actually metabolically active tissue capable of emitting powerful hormonal and inflammatory signals – and logically, the more fat we have on our body, the more harmful pro–inflammatory substances it can produce. The over–production of a particular substance called tumor necrosis factor–alpha (TNF–alpha) is directly associated with our level of body fat, and is thought to be a major cause of insulin resistance.

Study Link – Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor–alpha.

Quote from the above study:

Insulin resistance is a fundamental defect that precedes the development of the full insulin resistance syndrome as well as beta cell failure and type 2 diabetes. Tumor necrosis factor–alpha (TNF–alpha), a paracrine/autocrine factor highly expressed in adipose tissues of obese animals and human subjects, is implicated in the induction of insulin resistance seen in obesity and type 2 diabetes.

Exactly how TNF–alpha causes insulin resistance is the subject of some debate, but the general process is though to occur as follows: TNF–alpha causes an over–abundance of fatty acids to be released in adipocytes (fat cells). Of course, the adipocyte, like any other cell, needs fuel to operate, but an excess of these fatty acids will “gum up the works,” so to speak – impairing the oxidation of glucose, and overall mitochondrial function. When the fat released as a result of TNF–alpha overwhelms the fuel needs of the fat cell (which occurs relatively easily), the fatty acids are then released into the bloodstream to be used by other organs and tissues of the body.

In lean, healthy individuals, the insulin released in response to dietary carbohydrates should inhibit such a release of fat from the fat stores (we only need one source of fuel at a time, after all). But because of inflammatory mediators such as TNF–alpha, this signaling function of insulin doesn’t work properly. This is why insulin resistance almost always increases in direct parallel with a person’s level of body fat.

As a result of insulin resistance, diabetics and overweight individuals are constantly releasing fat into the bloodstream whether glucose and insulin are present or not – a major reason why blood levels of free fatty acids and triglycerides are almost always chronically elevated in diabetics.

Because fats can only be “burned” in the mitochondria, fatty acids inhibit the mitochondrial oxidation of glucose throughout the body (the competition between fats and glucose as fuel sources for the mitochondria is known as the Randle effect, or, the glucose–fatty acid cycle). And because the mitochondria are metabolizing a nearly limitless supply of fatty acids, in diabetes, the metabolism of glucose is largely inhibited. This, logically, causes the blood sugar to rise, and remain elevated, even in the presence of insulin.

We’ve seen previously that magnesium has the ability to lower blood lipids:

Study Link – Can dietary magnesium modulate lipoprotein metabolism?

Quote from the above study:

After 12 weeks, there was a significant decrease in total serum cholesterol (10.7%), low–density–lipoprotein ( LDL ) cholesterol (10.5%) and triglyceride (10.1%) in [the group receiving magnesium] compared to the values at entry to the study…

It’s likely that magnesium achieves this, in part, by reducing the levels of inflammatory chemicals (e.g. tumor necrosis factor–alpha) which cause the uncontrolled release of fatty acids into the blood stream. As evidence, numerous animal and human studies have shown that levels of tumor necrosis factor (and levels of many other inflammatory cytokines) are elevated in direct relation to the degree of magnesium deficiency:

Study Link – Elevated concentrations of TNF–alpha are related to low serum magnesium levels in obese subjects.

Quote from the above study:

Obese subjects exhibited higher serum concentration of TNF–alpha (p = 0.002) and lower serum magnesium levels (p < 0.0001) than lean and overweight subjects… These data shows that low serum magnesium levels and elevated TNF–alpha are related in the obese subjects.

Study Link – Magnesium–deficiency elevates circulating levels of inflammatory cytokines and endothelin.

Quote from the above study:

We have developed two rodent models of diet–induced magnesium–deficiency in which histologically defined cardiac lesions can be induced within two to three weeks. During the development of these lesions, the magnesium–deficient animals exhibit circulating cytokine levels which are indicative of a generalized inflammatory state. Dramatic elevations of the macrophage–derived cytokines, IL–1, IL–6, and TNF–alpha together with significantly elevated levels of the endothelial cell–derived cytokine, endothelin, were detected in the plasma of these animals.

Animal studies have even shown that the addition of magnesium to a high–fat, high–sugar diet prevents the development of insulin resistance and obesity in animal studies. The researchers attributed this effect, in part, to the reduction in TNF–alpha levels:

Study Link – Effects and Mechanisms of Magnesium on Obesity in Rats Fed with High Fat and Sucrose Diet.

Quote from the above study:

Mg can control the development of obesity, meliorate metabolism and insulin resistance, probably through regulating the level of TNF–α and the activity of NOS.

Magnesium It seems clear from the relevant research that magnesium is a fundamental factor in ensuring healthy blood–sugar control. Yet countless millions of Americans never suspect that their chronic sub–optimal magnesium intake may be largely responsible for their steadily–increasing weight gain, and accompanying increases in blood glucose and triglycerides. Though magnesium has yet to receive even a fraction of the mainstream media attention often lavished upon nutrients such as calcium, Vitamin C, and most recently, Vitamin D, bioavailable magnesium supplements (i.e., magnesium supplements which are well–absorbed into the bloodstream and into the body’s cells) represent the perfect example of a nutritional intervention uniquely geared to fill a major gap in our modern food supply. In many cases, the benefits of magnesium supplementation can be of life–altering significance.


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