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Scientifically formulated and clinically tested nutritional supplements

Alan B. McDaniel, M.D.
March 16, 2003

New concepts link adult onset (type II) diabetes, obesity, heart disease, stroke, polycystic ovarian syndrome, PMS and dysmenorrhea, abnormal cholesterol and blood lipids and thyroid dysfunction into a unified etiological framework of insulin resistance, which responds well to management with diet and supplements.

Insulin resistance is an ancient problem, the impact of which has only recently been recognized. We are witnessing a revolution in the understanding of diabetes mellitus. This new comprehension allows health care professionals to see the connections between many seemingly unrelated problems. If we approach these problems from the causal level, we're best able to help our patients.

In the 1950's, doctors appreciated that there are two types of diabetes. In type I or "juvenile onset" diabetes, the beta islet cells of the victim's pancreas had been destroyed so he was unable to make any insulin. With no insulin, it was not possible to move glucose from his blood into his cells. In effect, the cells of his body starved to death while his blood sugar was amazingly high.

In type II or "adult onset" diabetes, the situation was different and misunderstood. It had been believed that the patient simply had become so fat that his pancreas was unable to make sufficient amounts of insulin to keep his blood sugar down in the normal range. This is not the case. In the late 1960's, endocrinologists were confronted with a paradox. Having developed a laboratory test to measure the levels of blood insulin, researchers found that adult-onset diabetics had lots of insulin--in fact, even more than average in most cases. When I was in medical school in 1974, our professor had no explanation for this phenomenon.

In the early 1980's, a professor at Stanford University named Gerald Reaven was able to prove that type II diabetes is caused by resistance to insulin. Since then, an abundance of research material proves that diabetes develops not suddenly but in a sequence. Initially, the insulin-resistant person simply requires a little more insulin than usual to move glucose from his blood into the cells and maintain a normal blood sugar. Over the years, his resistance to insulin becomes gradually worse and he requires increasing amounts of insulin to maintain normal blood sugar. Finally, the patient produces a maximal amount of insulin and if his resistance gets worse, his blood sugar will then begin to rise. Doctors have created a set of guidelines to define "diabetes" which are based on abnormal levels of blood sugar. Until recently, we believed that there was no cause for concern as long as the patient had not crossed that threshold. That was before we realized that different organs have varying degrees of insulin resistance and sensitivity.

Please consider an analogous metaphor. A patient with insulin resistance might be compared to an old man with a hearing loss. As his hearing loss becomes worse, he needs to turn the volume of his television set louder and louder. Eventually, the volume reaches the maximum and when his hearing becomes even worse, he begins to miss some of the information. The old fellow might think that he was fine, as long as he could turn the volume up loud enough to hear everything. The problem is that there are other people in the room with normal hearing. They're being deafened by the television set.

In the last 10 years, research has shown that there are five different types of insulin receptors/glucose transport mechanisms. Different organs have different types and these different types have varying degrees of resistance. This means that some organs may be highly resistant to insulin while others are quite sensitive. This discovery has radically changed our understanding of the significance of insulin resistance and hyperinsulinemia (elevated blood levels of insulin).

We find that our skeletal muscles, which account for 80 to 90 percent of all insulin-stimulated glucose uptake, are very resistant to insulin, and the receptor/uptake mechanisms of the pancreatic cells that produce insulin and the liver, which balances sugar and fat, are even worse. These critical organs and tissues seem to be largely responsible for hyperinsulinemia.

On the other hand, the brain has excellent receptor/uptake mechanisms and is less resistant to insulin. The ovary also is very sensitive to elevated levels of insulin. It seems inevitable that a number of other tissues will found to be similarly vulnerable to the effects of high circulating insulin levels. Now let us examine the physiologic effects of insulin.

Insulin is a hormone that stimulates the transport of glucose from the blood into the cells. Glucose, of course, is the fundamental fuel from which we derive the energy to stay alive. Without insulin, the cell cannot take up glucose and will "starve." Insulin has a number of other metabolic effects, however. It activates anabolism (the body builds itself) through stimulating glucose utilization--forming glycogen for storage and converting glucose into both protein and fat. Moreover, insulin moves fat from circulation into storage. It then stimulates the creation of new triglycerides within the fat tissue and liver. Insulin also increases the synthesis of new protein and inhibits catabolism (the body breaking itself down). Insulin blocks the utilization of stored glycogen and blocks gluconeogenesis--the creation of new glucose. Insulin reduces the mobilization and utilization of free fatty acids for energy. Insulin lowers blood sugar levels. Insulin raises your circulating lipids (cholesterol and triglycerides) and makes you obese, particularly in the midsection.

As we review this impressive list of possible effects of the hormone insulin, consider the potential effects of hyperinsulinemia upon normally sensitive cells. Because the brain has normal insulin sensitivity, one can feel many symptoms when blood insulin levels are high but blood sugar levels are normal. In short, the brain does not have enough sugar to balance the high amount of insulin and therefore feels hypoglycemic. In addition to the many well-known symptoms of low blood sugar, the patient may suffer from dizziness, panic attacks and even migraine headaches. Unfortunately, many patients who suffer from this have gone without a diagnosis. Coming to their physicians complaining of low blood sugar, their blood sugar was measured--and it was normal. The true problem was hyperinsulinemia, but no one understood that. The unfortunate patient was sent home without an accurate diagnosis.

At this point, the picture becomes more complex. We will examine some of the specific effects of hyperinsulinemia on the other parts of the body. High levels of insulin and relatively low blood sugar both strongly stimulate the brain to increase the production of cortisol, the most potent steroid hormone. Cortisol increases the rate of metabolism, raises blood sugar and is our best response to chronic stress. It seems that many patients with insulin resistance and hyperinsulinemia have chronically increased adrenal output--often above levels that are considered normal. Although a discussion of the effects of elevated cortisol considerably exceeds the scope of this discussion, we should note that a high level of steroid production may have a number of significant consequences. These include depletion of progesterone (which is a precursor of cortisol) and inhibition of conversion of the thyroid pre-hormone T4 into its active form, T3. Many of my patients also appear to have depleted adrenal functional reserve in a pattern that is seen among marathon runners who have over-trained and patients with post-traumatic stress disorder. I believe this is caused by nutritional depletion through chronic hyperfunction.

The ovaries are very significant targets for hyperinsulinemia. This has been very well documented in the medical research literature. Chronically high levels of insulin can stimulate the vulnerable ovaries to form multiple cysts causing Polycystic Ovarian Syndrome. At the cellular level, the ovaries undergo "theca cell metaplasia" and increasingly look like testicles. They also act like testicles, producing excessive amounts of testosterone and androgens--steroid sex hormones that have a masculinizing effect. The woman's body does its best to convert these androgens to estrogen and therefore women have increasingly robust levels of both estrogens and androgens. This over-abundance seems to be associated with the early onset of menarche. In addition, combined with the depletion of progesterone (by the adrenal production of cortisol), this estrogen excess creates significant hormone imbalances. Patients have mood swings, headaches, fatigue, sugar cravings and other symptoms associated with PMS. Because of progesterone depletion, the length of the monthly cycle may be abnormal and due to relatively high estrogens, cramps, heavy flow and clotting are increased. With prolonged over-production of androgens, acne and hair on the face and elsewhere are increased. Other consequences of elevated estrogen/depleted progesterone could include uterine fibroids and fibrocystic breast disease. Finally, hyperinsulinemia causes reduced levels of sex hormone binding globulin (SHBG). This is a particularly unfortunate situation, because it confounds the less-expensive blood tests that are commonly employed and doctors can miss the diagnosis.

Because of the effects of hyperinsulinemia on the metabolism of sugar and fat, patients with insulin resistance have a seven-fold increased risk of a heart attack. Similarly, their risk of stroke is also increased seven times. Among diabetics, there is a substantial risk of kidney failure, perhaps through the effect of insulin resistance. This is a good time to note that not all patients with insulin resistance and hyperinsulinemia will develop diabetes mellitus. In fact, the presence of insulin resistance increases a person's risk of developing type 2 diabetes by seven fold--the same as the risk of heart attack and stroke. We must understand that insulin resistance causes a spectrum of disease--many seemingly interrelated problems which have a common cause. Fortunately, most patients will not suffer every consequence of their insulin resistance. Some people suffer none at all.

Although not supported in the medical literature, it is my impression that patients with insulin resistance suffer more from symptoms of allergy and immune hypersensitivity. I believe this is caused by the activation of the immune system, which seems to be a result of this process. In addition, the patients appear to suffer from reduced tolerance to pre-existing allergic symptoms as their total load (the total immunologic and metabolic burden they must bear) is increased. These allergies seem to be expressed more through the late and delayed immune responses (type II, III and IV) than through the immediate hypersensitivity or hay fever (type I) response. Unfortunately, 60 percent of allergists in the U.S. feel that late and delayed immune responses are clinically inconsequential.

This leads us to the consideration of "the yeast connection." In medical circles, this has been highly controversial and generally reviled. Among complementary healthcare providers, the treatment described first by Truss and elaborated by Crook has been found to be highly effective. Now that we understand insulin resistance, this apparent discrepancy can be understood. In my opinion, many patients who were felt to have a yeast-related problem suffered primarily from insulin resistance. A careful review of the symptoms in Dr. Crook's "Candida questionnaire" supports this idea. Moreover, the "Candida control diet" happens to be an excellent diet to manage hyperinsulinemia. The recommendations for vitamins and nutritional supplements nicely replenish many of the deficiencies that have developed among patients whose metabolism has been overstimulated by hyperinsulinemia and depleted by the standard American diet (SAD). For the record, many patients are indeed infested with fungus to which they are allergic--primarily a late or delayed type hypersensitivity response. The Candida protocol works very nicely for these patients but their most important underlying problem may be insulin resistance rather than yeast overgrowth.

When Dr. Reaven described this pathological constellation, which he originally called "Syndrome X" and is now more commonly known as "the Metabolic Syndrome," he noted an increased prevalence of autoimmune thyroiditis, which may be a manifestation of the overly-stimulated immune system. I find that many patients with this problem also suffer from insufficient conversion of the thyroid pre-hormone T4 into the active form, T3. This may be manifested in blood tests as an unfavorable ratio of T3 to reverse T3. Again, a detailed discussion of this condition exceeds the limitations of this paper but the association between insulin resistance and thyroid hormone dysregulation seems to be quite significant. Research has shown that T3 is reduced and reverse T3 is increased among patients who suffer from starvation (low blood sugar?), stress and elevated steroids. I believe that this is relevant to patients with insulin resistance and hyperinsulinemia, among whom all of these problems are increased.

A report published in the January 16, 2002 issue of JAMA demonstrates that insulin resistance is seen in only 3% of 20 year-old adults and may be found in up to 40% of people in their seventies. Although many environmental factors influence the age of development and severity of clinical expression, insulin resistance is basically an inherited condition. It seems to represent a mutation that is transmitted in an autosomal dominant fashion. If 20 to 40% of our population has this genetic predisposition to insulin resistance, is there reason for it? Indeed, there is.

Consider the situation of our ancestors more than 50,000 years ago. Food was not always in abundant supply and the human population was vulnerable to starvation, particularly in the winter. Those most likely to survive were the ones who had gained the most body fat during the months of abundance. As we've seen, insulin resistance predisposes to increased fat storage and obesity (following sugary or starchy meals), which would have helped our effected ancestors survive in the harsh climate of the Ice Age. The Ancients ate very little sugar or starch. They found berries in the spring and fruits in the fall. With luck, they could occasionally hustle up some honey in a beehive. Insulin resistance helped them to maximize the "benefit" from these foods – getting fat.

The results of such environmental selection may still be seen among the Native American Pima tribe. They have adapted to living in a barren desert. Unfortunately, eating the standard American diet, 80% develop type 2 diabetes mellitus by the age of 40. The same genes that helped them survive when there was very little food are causing major health problems now that their diet is full of simple carbohydrates.

Among ancient populations, survival of the tribe (and of the species) was also determined by reproductive ability. Remember that the goddess figurines of the Old Stone Age seem to uniformly represent pregnant women. Modern American girls with insulin resistance seem to reach menarche at an earlier age than do their peers. I believe that the genetic predisposition to insulin resistance conferred a reproductive advantage as well as a survival advantage to those who were effected. The sooner a young woman could bear children, the more it benefited her tribe and her species.

It seems that for our ancient ancestors, there was no "down side" to insulin resistance. Among modern American women, ovarian cystic disease and infertility seem to declare themselves in the mid-to-late twenties. By that age, our ancestors would have already had 10 children and have been past the reproductive age. Very few ancient people lived very far into their 30's, so that death by other causes intervened before they could develop diabetes, heart disease or stroke. Because there were few sugars and starches in their diet, insulin resistance was a benefit rather than a problem.

Only in the last 150 years, just the "twinkling of an eye" in the history of the human species, have dietary sugar and starch been available to any but the most wealthy. In previous centuries, only the wealthy could afford to be fat. They ate a rich, sugary diet and did not have to exercise or work physically. The common people ate meat, vegetables and whole grains and physically labored to make their living. Today, rich people eat live foods and whole grains and exercise at the health club to stay slender while average people eat a starchy diet and get very little exercise. The sugar and refined carbohydrates that once were the prerogative of the rich are now the cheapest foods at the grocery stores. As the American diet has changed, so has our health. Americans now lead the world in obesity, diabetes and heart disease.

There is considerable controversy regarding the best way to diagnose insulin resistance and hyperinsulinemia. Some doctors use fasting blood tests taken first thing in the morning. I find this to be insufficient. Until a better method has been determined, I recommend performing an old-fashioned glucose tolerance test with an important modification. A patient comes into the laboratory having not eaten anything for eight hours. A blood specimen is drawn to measure both glucose and insulin. The patient is next given a drink containing 75g of glucose, which they chug-a-lug as though at a fraternity party. Blood specimens are drawn at 1/2 hour, 1, 2, 3 and 4 hours afterwards. The measurements of blood sugar and insulin may be compared against excellent data published by Dr. Reaven in 1987. Most authors agree that blood insulin should not rise above the level of 100 uU/mL. In the future, I expect that we will examine the ratio of insulin to glucose as a short cut.

The treatment for hyperinsulinemia involves four primary limbs. First and foremost, the patient must eliminate sugar, starch and most fruit from their diet. In the early 1980's, we heard a lot about the "caveman diet." For the 20 to 40 percent of Americans affected, this is a pretty good diet plan. The proliferation of diet plans that minimize sugar and starches demonstrates the importance of this approach. Diets as academic as Sears' Enter the Zone and the Mayo clinic diet, popular as Protein Power or Sugar Busters or seemingly so fluffy as Suzanne Sommers' all agree in the same basic principles. That is because this works.

The second limb of treatment is nutritional. Supplementation with chromium and vanadium may significantly improve sensitivity of the insulin receptor/uptake mechanism. About half of my patients who take these report very gratifying improvement in their sugar cravings. My experience with other supplements like alpha-lipoic acid is limited.

The third limb of treatment is physical. A recent study of diabetics proved that even rather gentle exercise performed regularly will substantially improve insulin resistance. I advise a 20-minute walk at least five times a week and warn people against over-doing it. Chronic strenuous exercise can deplete the adrenal reserve as noted above. Leave the "no pain, no gain" philosophy to the Marines.

In addition, researchers at the University of Chicago have shown that sleep deprivation worsens insulin resistance. Americans need more sleep than we have been getting. At the turn of the last century, the average person got 9 hours sleep every night. That was before the Internet and the Tonight Show. I recommend that my patients schedule at least 7 1/2 hours in a darkened room every day.

The last option, unfortunately, is often the only one embraced by medical doctors. Certain drugs may improve the sensitivity of insulin receptors, including Glucophage and Avandia. I find that these are useful, depending upon the severity of the patient's hyperinsulinemia. They have to be used carefully, because they can cause lots of G.I. side effects if the patient is eating a lot of sugar and starch. Similarly, they can work too effectively and create hypoglycemia.


In summary, we are in the midst of a revolution. Doctors are beginning to understand the causes of type 2 diabetes and more importantly, the significant pathology that can be consequent to insulin resistance--even in the absence of overt diabetes. We must understand that this is a spectrum of clinical problems manifested as a consequence of insulin resistance. Only the most unfortunate patient will have all of these problems. Many times, one can take a detailed family history and find various relatives showing some or other of the associated problems. This is a little bit like a card game. The patient is playing with the deck of cards labeled "insulin resistance." Whether they show diabetes, obesity, heart disease, polycystic ovarian syndrome or what ever depends simply upon how the cards fall. Of course, lifestyle may significantly effect their result. Our job as health care providers is to recognize this problem at an early stage and teach the patient to apply "a stitch in time."

Alan B. McDaniel, M.D.
September 18, 2002
Revised October 23, 2002.

I need to write more about Gestational Diabetes, which is strongly correlated. A useful clue is often gained by asking about the size of a woman's babies.

Also conspicuously absent are comments about the relation between insulin resistance and hypertension (perhaps from the aldosterone-like effect of insulin?), Meniere's syndrome and obstructive sleep apnea, recently reported by both Hopkins and Penn.

It is also important to note that we must be careful in giving adrenal nutrition to these patients. Insulin stimulates the HPA axis to increase ACTH secretion and thereby increase cortisol production. I suspect that just as insulin directly stimulates the ovaries, it may also the adrenal cortex. In these people, adrenal "glandulars" are very useful but women seem already to have excessive androgens, so I find it important to avoid use of DHEA. It is fine, however, and generally helpful to give DHEA to men with insulin resistance. Pregnenolone, in contrast, is extremely useful for effected women and generally should be avoided in men.
-- Alan.
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