Time is the substance from which I am made. Time is a river which carries me along, but I am the river; it is a tiger that devours me, but I am the tiger; it is a fire that consumes me, but I am the fire.

–Jorge Luis Borges, Argentinian author.

ging can accurately be described as a cellular energy crisis. As we age, our cells often produce energy ever–more inefficiently, and, over time, impaired energy production on a cellular level adds up to tissues and organs which function abnormally. Ultimately, this self–perpetuating energy crisis often results in age–related disease or general bodily degeneration.

Of course, each individual is a bit different with regard to exactly how these age–related changes manifest at advanced stages. One person may notice sore joints which ultimately progresses to arthritis, while another may notice mental decline – possibly the forerunner of an age–related dementia like Alzheimer’s disease, and still others may notice that their middle–age weight gain leads them down the path to metabolic syndrome, and the closely–related disorders of heart disease and diabetes.

But, no matter how varied the signs of aging may be, scientists are beginning to see that the cellular changes associated with aging are largely universal throughout our various tissues. It seems that long before any symptoms of aging develop, there occurs a fundamental shift in how our cells produce energy. In aging, progressive damage to energy producing cellular structures called mitochondria shifts energy production away from mitochondrial respiration, and towards glycolysis – a more primitive and inefficient means of energy generation.

In healthy cells, glycolysis is used to metabolize glucose into compounds which can be “burned” in the mitochondria to produce energy. Glycolysis is also relied upon to produce energy for short periods of time when oxygen isn’t readily available – such as during intense exercise. These are both normal, healthy functions of glycolysis, but, in aging and disease, our cells begin to shift towards what is known as aerobic glycolysis – in other words, they rely on glycolysis for energy production even when oxygen is present. Aerobic glycolysis is a clear indication that the mitochondria have somehow become damaged or defective, and can’t perform their proper function. This glycolytic shift not only produces energy inefficiently, but it also produces many harmful metabolic byproducts. Lactic acid (lactate), pyruvate, phosphate, and glycated proteins are formed as a result of glycolysis, and in a vicious cycle, these substances further inhibit mitochondrial function.

Fortunately, some nutritional substances involved in energy production, may be able to help us sustain or regain healthy mitochondrial activity. Creatine appears to be one such substance. On a molecular level, creatine has been shown to prevent many of the harmful cellular events which are caused by the shift to glycolytic metabolism. On an organismic level, creatine supplementation has been shown to extend lifespan in animals, as well as to improve several markers of age–related degeneration.

When we understand the universal cellular changes which cause aging, only then can we appreciate how powerful a simple nutritional substance like creatine can be in helping us combat the process. Continuing with our creatine Q & A, we’ll now examine more of the cellular changes associated with aging, and more of the far–reaching anti–aging benefits of creatine.

For more background information, please read the previous Integrated Supplements Newsletter on the anti–aging effects of creatine.

Q. We discussed how the glycolytic shift in metabolism is akin to hyperventilation because, while oxygen is available, the mitochondria of our cells can’t utilize it properly. We also saw how panic disorder and anxiety are characterized by this sort of aerobic glycolysis. Do the disorders of aging display a similar metabolic shift?

A. Yes, a stunning number of them do. In fact, the shift towards glycolysis is now being recognized as a central factor in aging. If we can reduce aerobic glycolysis by keeping our mitochondria healthy – consuming oxygen and producing carbon dioxide as they should – we may be able to forestall many of the debilitating effects of old age. To see how, it will help to take a look at some age–related disorders in relation to mitochondrial function:

Cancer and Glycolysis

In the 1920’s, Nobel laureate, Otto Warburg, noted that malignant growths including cancerous tumors, exhibited a near–universal shift to glycolytic metabolism. It’s known that, normally, glycolysis is inhibited by the presence of oxygen (which is known as the Pasteur effect), but in cancerous tissue, glycolysis and the production of lactic acid predominates even when oxygen is available (this is known as aerobic glycolysis, or also, the Warburg effect).

Warburg figured that the cells were resorting to the more “primitive” glycolytic means of energy production out of necessity when the mitochondria were damaged – the result ultimately being the growth of cells uniquely suited to such an environment, i.e., a tumor or cancerous growth. It’s well–known that cancer cells thrive on glucose, and that cancer cells are equipped to proliferate rapidly in the presence of lactic acid. Knowing these facts, Warburg hypothesized that the cause of cancer was fundamentally due to mitochondrial dysfunction which shifted the cell metabolism towards glycolysis, and away from the oxidation of glucose which takes place in the mitochondria.

Over 80 years after Warburg’s initial hypothesis, it’s still well–accepted that cancerous cells exhibit high rates of glycolysis, but there has been some debate over whether mitochondrial damage, and the resulting increase in glycolysis, is actually the cause of cancer, or merely an effect. Conventional thinking on cancer in recent decades has attributed the cause of cancer, not to mitochondrial damage, per se, but to genetic mutations. But we now know that, even if genetic mutations play a fundamental role in cancer development, this doesn’t refute Warburg’s theory. As we have seen, damage to the genes of the mitochondria (not the nucleus) is sufficient to cause major mitochondrial damage – and a subsequent increase in glycolysis, cell dysfunction, and ultimately, cancer.

Such mutations of mitochondrial DNA are, in fact, among the earliest identifiable markers of cancer development:

Study Link – Analysis of potential cancer biomarkers in mitochondrial DNA.

Study Link – Mitochondrial DNA mutations in human cancer.

And it’s important to remember that inefficient mitochondrial energy metabolism often precedes and causes genetic mutations in the mitochondria in the first place.

In recent years, as scientists have gained a greater understanding the effects of mitochondrial dysfunction, Warburg’s theory of cancer development has gained increasing validation:

Article Link – New Findings Support Warburg Theory Of Cancer.

Study Link – Cancer's Molecular Sweet Tooth and the Warburg Effect.

Interestingly as it relates to cancer, one of the functions of healthy mitochondria is to sometimes trigger apoptosis, or, the controlled destruction of abnormal cells. We’ve discussed the harmful effects of oxidative stress in previous newsletters, and it seems that when levels of oxidative stress produced by the mitochondria reach a critical point in the cell, this can set the process of apoptosis into motion.

Under ideal conditions, apoptosis continually prevents minor cellular defects and cellular damage from spiraling into full–blown metabolic disorders. But when mitochondria are severely, or chronically damaged, as they are in cancerous cells, this “self–destruct” mechanism doesn’t always work properly. In a sense, the shift to glycolysis is another way in which the cell tries to protect itself from high amounts of oxidative stress. Logically, oxidative stress requires oxygen, and where glycolysis doesn’t require oxygen as mitochondrial respiration does, aerobic glycolysis is likely to be our body’s desperate attempt to limit oxidative stress.

But, as we know, glycolytic metabolism is harmful in its own right. In a vicious cycle, damage to the mitochondria causes an increase in oxidative stress, which causes a shift to glycolysis, and glycolysis further inhibits mitochondrial function including the ability to trigger apoptosis (the inhibition of mitochondrial function by glycolysis is known as the Crabtree effect, which is very pronounced in cancerous cells).

Because it causes the loss of the cellular “self–destruct” mechanism in the mitochondria, the shift to glycolysis is now thought to account for the “immortality” of cancer cells:

Study Link – Protection from oxidative stress by enhanced glycolysis; a possible mechanism of cellular immortalization.

Quote from the above study:

As enhanced glycolysis is a distinctive and prominent feature of cancer cells (termed the Warburg effect), our findings disclosed a novel aspect of the Warburg effect: the connection between senescence [aging] and oxidative stress.

Much of conventional and even alternative cancer treatment centers, in essence, on “killing” cancer cells – but these therapies almost always fail to rectify the fundamental respiratory defect underlying cancer in the first place. Conceptually, if we view the goal of cancer therapy to be “cell killing,” then finding ideal anti–cancer agents – substances which “kill” cancer cells while leaving healthy cells alone – will seem almost impossible. But, when we view the goal of cancer therapy to be the restoration of healthy mitochondrial function, it’s easy to see how certain interventions will help healthy cells thrive, while defective ones perish. In other words, improving mitochondrial function will help healthy cells stay that way, and will help damaged cells kill themselves as they constantly do in healthy individuals.

Scientists are now discovering that the damage incurred by mitochondria in cancer cells may not be irrevocable as was once believed. That is, certain therapies may be able to “re–energize” the mitochondria, allowing cellular function to resume normally (including the “self–destruct” mechanism which has gone awry in cancer). Instead of “killing” cancer cells via indiscriminately toxic means, one of the goals of “mitochondrial” therapies is to help to shift energy production away from glycolyis, thus enhancing the proper flow of energy through the mitochondria.

As a relatively crude example, the drug dichloroacetate (DCA) is known to inhibit glycolyis. Canadian researchers created quite a stir a few years ago when they tested DCA in vitro and in animal models of cancer with some success:

Article Link – Cheap, 'safe' drug kills most cancers.

Quote from the above article:

Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumors in rats deliberately infected with human cancer also shrank drastically when they were fed DCA–laced water for several weeks.

Because DCA inhibits glycolysis in healthy cells as well as cancerous ones, it’s not surprising that DCA has toxic side effects (although it’s thought to be relatively less toxic than other cancer therapies). Of course, from a general health standpoint, we don’t want to inhibit all glycolysis as DCA does – but these findings are further evidence that we do want to prevent the switch to aerobic glycolyis that occurs when mitochondria are damaged, or when cellular energy production is severely hindered.

The possible effectiveness of DCA in cancer is simply a clue that perhaps we may want to investigate safer nutritional approaches to support efficient mitochondrial function.

Research is increasingly showing that the energy nutrient creatine may be just such a substance. Some preliminary cancer studies, for example, have shown promising results when creatine was administered:

Study Link – Inhibition of rate of tumor growth by creatine and cyclocreatine.

Quote from the above study:

For mammary tumor Ac33tc, the growth inhibition during 24 days after the implantation was approximately 50% for both 1% cyclocreatine and 1% creatine, and inhibition increased as creatine was increased from 2% to 10% of the diet. For the other rat mammary tumor (13762A), there was approximately 35% inhibition by both 1% cyclocreatine and 2% creatine.

Interestingly, in the above study, both creatine and a creatine antagonist (cyclocreatine) were effective in reducing tumor growth rates.

Note: The reason for the effectiveness of creatine and its antagonist may have something to do with how these substances impact glycolysis; or, similarly, it may have to do with phosphate metabolism. Both compounds are able to scavenge inorganic phosphate (creatine combines with phosphate to form phosphocreatine, and similarly, cyclocreatine combines with phosphate to form phosphocyclocreatine). Elevated levels of free phosphate have been shown to play a role in some cancers, and many phosphate–associated enzymes are known to be involved in cancer progression.

Of course, it’s far too early to draw any firm conclusions from such limited data (meaning that there is not yet sufficient evidence for advocating creatine or its analogs as treatments or preventatives for cancer), but such research may eventually provide further insight into cancer, as well as creatine’s role in supporting proper mitochondrial function.

From a general anti–aging perspective, it’s clear that creatine helps to maintain the energy “charge” of the cell – acting as a substrate to rapidly regenerate ATP. The high–energy cell has several mechanisms by which to protect mitochondrial function, and is therefore less apt to be significantly damaged by various stressors. For instance, as we referenced in the previous newsletter, creatine supplementation has been shown, in some in vitro studies, to prevent the damage to mitochondrial DNA induced by ultraviolet radiation:

Study Link – Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences.

The fact that creatine can exert such a protective effect on the mitochondria makes sense in the light of other research showing creatine to enhance mitochondrial function – and consequently, to reduce the products of glycolysis.

For example, the following study showed that creatine supplementation in men increased carbohydrate oxidation with a subsequent trend towards an increase in respiratory exchange ratio (as measured by the ratio of carbon dioxide exhaled versus oxygen inhaled). As we’ve seen, carbohydrate oxidation (the metabolism of carbohydrates using oxygen) takes place in the mitochondria, with carbon dioxide being a major product of the process. Such an increase in carbon dioxide production and respiratory exchange ratio is clear evidence that creatine supplementation can lead to an increase glucose metabolism by the mitochondria.

Study Link – Creatine supplementation influences substrate utilization at rest.

Quote from the above study:

Carbohydrate oxidation was increased by creatine (8.9  ± 4.0%, P < 0.05), whereas there was a trend for increased respiratory exchange ratio after creatine supplementation (0.03 ± 0.01, P  = 0.07).

And, in keeping with these findings, other studies have shown that creatine increases glucose oxidation, and reduces lactate production in isolated skeletal muscle cells:

Study Link – Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells.

Quote from the above study:

We conclude that 48 h of creatine supplementation does not alter insulin–stimulated glucose uptake and glucose metabolism; however, it activates AMPK, shifts basal glucose metabolism towards oxidation and reduces lactate production in L6 rat skeletal muscle cells.

So, these various lines of research all point to a similar mechanism of action. It seems that creatine supplementation may help to maintain the healthy function of our mitochondria – possibly allowing us to avoid cumulative mitochondrial damage, thus reducing the “defense mechanism” shift to aerobic glycolysis.

Diabetes and Glycolysis

Insulin resistance occurs when the cells of our body (specifically, muscle, fat, and liver cells) no longer respond properly to insulin. In healthy people, insulin triggers the uptake of glucose from the bloodstream into these cells, but, in aging and disease, insulin resistance increases, which is one reason why blood sugar levels often become chronically elevated.

Of course, insulin resistance is well–known to be the metabolic forerunner of diabetes – and in both insulin resistance and diabetes, again, we find that cellular energy production shifts towards glycolysis and away from mitochondrial respiration.

The following study provides clear evidence that the shift towards glycolytic metabolism parallels the severity of insulin resistance. Those with type 2 diabetes (formerly called non–insulin–dependent diabetes mellitus, or NIDDM, as in the following study) exhibited the highest levels of glycolytic enzymes, followed by obese individuals who weren’t (yet) diabetic, followed by lean individuals:

Study Link – Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM.

Quote from the above study:

In summary, an imbalance between glycolytic and oxidative enzyme capacities is present in NIDDM subjects and is more severe than in obese or lean glucose–tolerant subjects. The altered ratio between glycolytic and oxidative enzyme activities found in skeletal muscle of individuals with NIDDM suggests that a dysregulation between mitochondrial oxidative capacity and capacity for glycolysis is an important component of the expression of insulin resistance.

Along the same lines, other studies have concluded that it is fundamentally mitochondrial dysfunction which leads to insulin resistance:

Study Link – Role of Mitochondrial Dysfunction in Insulin Resistance.

Quote from the above study:

…when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption [indicative of mitochondrial function] is low, leading to an increased production of superoxide anions [a type of free radical]. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications.

But, regardless how convincing the research is, in the eyes of the general public, diabetes has yet to be recognized as fundamentally a mitochondrial disorder. In reading much of the popular literature on diabetes and insulin resistance, 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 diabetes. It can also blind a person to simple and effective strategies 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 energy producing mechanisms inside the cell.

For example, we know 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 in adipose (fat) tissue:

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 obese 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 diverted away from the mitochondria, and towards glycolysis – with large amounts of lactic acid produced as a result. Diabetics and obese individuals are known to produce very large amounts of lactic acid:

Study Link – Plasma lactate concentration in obesity and type 2 diabetes.

Quote from the above study:

Under these conditions, plasma lactate concentration was lowest in the non–obese group with normal glucose tolerance (0.81 +/– 0.07 mmol/L), highest in the obese subjects with Type 2 diabetes (1.46 +/– 0.14 mmol/L), and intermediate in obese individuals with normal glucose tolerance (1.17 +/– 0.13 mmol/L). All three groups were significantly different from each other. In addition plasma lactate concentrations were associated with both fasting plasma glucose and glycated haemoglobin.

And considering that the diabetic metabolism exhibits high rates of aerobic glycolysis and lactate production, it’s not surprising that diabetics are known to experience a notably increased rate of what’s called the Cori cycle. The Cori cycle is the metabolic process by which lactate (from lactic acid) is transported to the liver to be reconverted into glucose. Upregulation of the Cori cycle, by recycling lactic acid back into glucose, is yet another reason why blood sugar is chronically elevated in diabetes.

Study Link – Increased rate of Cori cycle in obese subjects with NIDDM and effect of weight reduction.

So, in the biological events leading up to diabetes, we can see an incredibly vicious cycle in which increased levels of bodyfat lead to increased inflammation and fatty acid release from fat cells. This nearly unlimited supply of fatty acids floods the bloodstream, impairs glucose oxidation, and increases both glycolysis and lactate production. This lactate causes even more fatty acids to be released, and is, itself, reconverted back into glucose which perpetuates the pernicious cycle.

To make matters still worse, many sugars and sugar metabolites which are formed during glycolysis are chemically reactive – they combine with cellular proteins and lipids to form substances called glycation products and advanced glycation endproducts (AGEs). Damaged cellular proteins such as these can wreak further havoc with metabolic function, and where diabetes exhibits such a large increases in blood sugar and glycolytic metabolism, it’s not surprising to see that diabetics produce a notably large amount of these AGEs:

Study Link – Advanced glycation end–products and advanced oxidation protein products in patients with diabetes mellitus.

Quote from the above study:

AGEs were elevated only in [type 2 diabetics].

In fact, one of the laboratory tests used to examine long–term glucose control in diabetics measures blood levels of a glycated protein from red blood cells called glycated hemoglobin, or HbA1C. And increasingly, researchers attribute various diabetic complications like kidney disease and cardiovascular disease, in large part, to the effects of the various glycation products known to be produced in diabetes:

Study Link – Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes.

Quote from the above study:

AGEs potently modulate initiating steps in atherogenesis involving blood–vessel wall interactions, triggering an inflammatory–proliferative process and, furthermore, critically contribute to propagation of inflammation and vascular perturbation in established disease. Thus, a better understanding of the biochemical mechanisms by which AGEs contribute to such processes in the vessel wall could be relevant to devise preventive and therapeutic strategies for diabetic atherosclerosis.

Q. Where creatine improves the efficiency of energy production, can creatine help diabetics control their blood sugar?

A. To the best of our knowledge, there hasn’t yet been much research on creatine in diabetics – so it’s impossible to say at this point.

In healthy people and animals however, some studies have shown creatine to help maintain a healthy blood sugar.

Animal studies published as far back as 1929 have shown that oral creatine supplementation can have an insulin–sensitizing and blood sugar–regulating effect. Unlike drugs used to lower blood sugar, creatine appears to be completely non–toxic, and in the following study, even very high doses of creatine were unable to lower blood sugar to dangerously low hypoglycemic levels. Its lack of side effects, even at high doses, may be a clue that creatine is a part of the body’s natural mechanism for ensuring healthy blood sugar levels.

Study Link – The Effect of Creatine on the Blood Sugar.

The researchers summarized the results of the above study as follows:

1) Creatine given either subcutaneously or by mouth reduces the blood sugar of fasting dogs.

2) Creatine given with glucose in a glucose tolerance test diminishes or in some cases practically abolishes the rise in blood sugar.

3) Creatine is apparently non–toxic.

4) By administration of creatine it is impossible to depress the blood sugar to the point where convulsions occur.

5) A dog which otherwise excreted large quantities of glucose after glucose administration was “sugar–free” when creatine was given with the glucose.

One of the study’s authors even reported that after he himself consumed 98.4 grams of glucose along with 50 milligrams of creatine per pound of bodyweight (4 grams of creatine for a 176 lb man), amazingly, no rise in blood sugar occurred. From this study, it seems reasonable to guess that creatine plays a major role in stimulating the uptake and efficient metabolism of glucose by the cells. Some more recent studies seem to confirm that this is, indeed, the case.

We find that, combined with exercise, creatine may be able to improve glucose uptake into muscle cells. Exercise causes a protein called glucose transporter 4 (GLUT 4) to be increased on the surface of muscle cells (conversely, inactivity normally causes a reduction in GLUT 4 expression).

As its name implies, GLUT 4 transports glucose from the bloodstream to be stored in the cell (as the storage form of glucose, called glycogen). The increased expression of GLUT 4 as a response to exercise is one of the major reasons why exercise is so beneficial to people looking to keep their blood sugar under control – and it turns out that creatine taken in conjunction with exercise may be able to increase the expression of GLUT 4 on muscles cells more than exercise alone. Similarly, creatine may also be able to prevent the reduction of GLUT 4 expression which often accompanies inactivity.

Study Link – Effect of Oral Creatine Supplementation on Human Muscle GLUT4 Protein Content After Immobilization.

Quote from the above study:

We concluded that 1) oral creatine supplementation offsets the decline in muscle GLUT4 protein content that occurs during immobilization, and 2) oral creatine supplementation increases GLUT4 protein content during subsequent rehabilitation training in healthy subjects.

Study Link – Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT–4 content and glucose tolerance in humans.

Quote from the above study:

We conclude that creatine intake stimulates GLUT–4 and glycogen content in human muscle only when combined with changes in habitual activity level. Furthermore, combined protein and creatine supplementation improved oral glucose tolerance, which is supposedly unrelated to the changes in muscle GLUT–4 expression.

Creatine has even been studied as a compound with the potential to prevent glycation, and the formation of the previously mentioned advanced glycation end products. Where creatine may have the effect of improving glucose metabolism, researchers wondered what effect creatine would have on the glycation process. The following in vitro study found that creatine did, in fact, reduce the formation of glycated substances. The effects weren’t as significant as that of some blood sugar–lowering drugs, but the overwhelming safety of creatine gave the researchers reason to be optimistic about its future use in this regard.

Study Link – Substituted Guanidine Compounds as Inhibitors of Nonenzymatic Glycation in vitro.

Quote from the above study:

Pathologic effects of the process of nonenzymatic glycation are reflected in degenerative changes during ageing, chronic complications of diabetes mellitus and renal failure, and have also been recognized in some neurologic diseases, such as Alzheimer’s disease…Both agents, a–methylguanidine–acetic acid [creatine] and dimethylbiguanide, tested at concentrations of 2.5, 5, 10 and 20 mmol L–1, showed a concentration dependent inhibition of the glucose induced albumin glycation in vitro. The inhibiting effect of substituted guanidines was somewhat inferior (17%) to the effect of aminoguanidine inhibition (52%); however, the former substances are valuable for being safe for human use.

We’ve seen what an integral role fats and triglycerides play in diabetes, and another intriguing study showed that creatine may help to reduce blood lipids including triglycerides, and total cholesterol.

Study Link – High–performance capillary electrophoresis–pure creatine monohydrate reduces blood lipids in men and women.

Quote from the above study:

Significant reductions in plasma total cholesterol, triacylglycerols [triglycerides]and very–low–density lipoprotein–C occurred within the creatine monohydrate group.

Collectively, these studies hold promise for creatine use in diabetes, but it’s very important to remember the inflammatory component of insulin resistance and diabetes we spoke about earlier. Over 80% of diabetics are overweight, and excess body fat is constantly emitting pro–inflammatory and metabolism–disrupting chemicals. This inflammation is likely to be the primary factor which sets insulin resistance and the diabetic process into motion in the first place, as it triggers the constant release of fatty acids into the bloodstream. In studies using healthy individuals, or in in vitro studies, this major inflammatory burden is missing, or at least, lessened, making it difficult to speculate on whether creatine would have similar effects in those with diabetes.

So, as boring and cliché as the advice is, a healthy diet geared towards body fat reduction, along with regular exercise are likely to be the greatest contributing factors to reducing inflammation and improving blood sugar metabolism in those with insulin resistance or diabetes. Creatine can certainly be a part of any healthy supplement regimen, but it cannot be expected to make up for an unhealthy diet or lack of physical activity.

Although we looked at mitochondrial dysfunction and the accompanying glycolytic shift only in regard to cancer and diabetes, scientists have noted the same phenomenon running throughout all disorders of aging, including heart disease and neurological disorders like Alzheimer’s disease. As scientists continue to unravel the biology of aging, it appears more and more likely that protection against the major killers of our time will rely heavily on keeping our mitochondria functional and healthy.

In the past several decades, as our scientific knowledge has advanced at a breathtaking pace, the many seemingly disparate fields of biological research have simultaneously diverged upon a fundamental truth: that energy is the essence of life. By helping to maintain the high–energy state of the youthful cell, creatine is likely to be one of the many nutritional substances which can help us to forestall the ravages of age, and which can help us reach our full human potential.