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INSULIN RESISTANCE:
THE MAJOR PLAYER
OPRAH WINFREY HAS waged her weight loss battles publicly for several decades. At her heaviest, she weighed 237 pounds (107.5 kilograms). By 2005, she’d battled her way to a relatively svelte 160 pounds (72.6 kilograms). She was exultant. She’d cut her carbohydrates. She’d exercised. She had a personal chef and a personal trainer. She did everything “right.” She had every advantage not available to the rest of us. So why did she gain back 40 pounds (18 kilograms) by 2009? Why couldn’t she keep the weight off?
Why is long-standing obesity so difficult to treat?
Time dependence in obesity is almost universally understood but rarely acknowledged. Usually, obesity is a gradual process of gaining 1 to 2 pounds (0.5 to 1 kilogram) per year. Over a period of twenty-five years, though, that can add up to 50 extra pounds (23 kilograms). Those who have been obese their entire lives find it extremely difficult to lose weight. In contrast, people with recent weight gain have a much, much easier time dropping the excess pounds.
Conventional caloric theories of obesity assume that losing 10 pounds (4.5 kilograms) is the same experience whether you’ve been overweight for one week or one decade. If you reduce the calories, the weight will be lost. But this is simply not true. Likewise, the carbohydrate-insulin hypothesis makes no allowance for duration of obesity: reducing carbohydrates should cause weight loss, regardless of how long you’ve been overweight. But that’s not true either.
But the time frame matters a lot. We may try to downplay its effects, but the idea that long-standing obesity is much more difficult to treat has the stench of truth.
So we must acknowledge the phenomenon of time dependence. Obesity at age seventeen has consequences that reach decades into the future.1 Any comprehensive theory of obesity must be able to explain why its duration matters so much.
High insulin levels cause weight gain. Food choices play a role in raising insulin levels. But we are missing yet another pathway that increases insulin, one that is both time dependent and independent of diet: insulin resistance.
Insulin resistance is Lex Luthor. It is the hidden force behind most of modern medicine’s archenemies, including obesity, diabetes, fatty liver, Alzheimer’s disease, heart disease, cancer, high blood pressure and high cholesterol. But while Lex Luthor is fictional, the insulin resistance syndrome, also called the metabolic syndrome, is not.
HOW DO WE DEVELOP RESISTANCE?
THE HUMAN BODY is characterized by the fundamental biological principle of homeostasis. If things change in one direction, the body reacts by changing in the opposite direction to return closer to its original state. For instance, if we become very cold, the body adapts by increasing body-heat generation. If we become very hot, the body sweats to try to cool itself. Adaptability is a prerequisite for survival and generally holds true for all biological systems. In other words, the body develops resistance. The body resists change out of its comfort range by adapting to it.
What happens in the case of insulin resistance? As discussed before, a hormone acts on a cell as a key that fits into a lock. When insulin (the key) no longer fits into the receptor (the lock), the cell is called insulin resistant. Because the fit is poor, the door does not open fully. As a result, less glucose enters. The cell senses that there is too little glucose inside. Instead, glucose is piling up outside the door. Starved for glucose, the cell demands more. To compensate, the body produces extra keys (insulin). The fit is still poor, but more doors are opened, allowing a normal amount of glucose to enter.
Suppose that in the normal situation we produce ten keys (insulin). Each key opens a locked door that lets two glucose molecules inside. With ten keys, twenty glucose molecules enter the cell. Under conditions of resistance, the key does not fully open the locked door. Only one glucose molecule is allowed in. With ten keys, only ten glucose molecules are allowed in. To compensate, we now produce a total of twenty keys. Now, twenty glucose molecules are allowed in, but only because we have increased the number of keys. As we develop insulin resistance, our bodies increase our insulin levels to get the same result—glucose in the cell. However, we pay the price in constantly elevated insulin levels.
Why do we care? Because insulin resistance leads to high insulin levels, and as we’ve seen, high insulin levels cause obesity.
But what caused the insulin resistance in the first place? Does the problem lie with the key (insulin) or the lock (insulin receptor)? Insulin is the same hormone, whether found in an obese or a lean person. There is no difference in amino-acid sequence or any other measurable quality. Therefore, the problem of insulin resistance must lie with the receptor. The insulin receptor does not respond properly and locks the glucose out of the cell. But why?
To begin solving this puzzle, let us back up and look for clues from other biological systems. There are many examples of biological resistance. While they may not apply specifically to the insulin/insulin-receptor problem, they may shed some light on the problem of resistance and show us where to begin.
ANTIBIOTIC RESISTANCE
LET’S START WITH antibiotic resistance. When new antibiotics are introduced, they kill virtually all the bacteria they’re designed to kill. Over time, some bacteria develop the ability to survive high doses of these antibiotics. They’ve become drug-resistant “superbugs,” and infections from them are difficult to treat and can sometimes lead to death. Superbug infections are a large and growing problem in many urban hospitals worldwide. All antibiotics have begun to lose their effectiveness due to resistance.
Antibiotic resistance is not new. Alexander Fleming discovered penicillin in 1928. Mass production of it was perfected by 1942, with funds from the U.S. and British governments for use in World War II. In his 1945 Nobel lecture, “Penicillin,” Dr. Fleming correctly predicted the emergence of resistance. He said,
There is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non lethal quantities of the drug make them resistant. Here is a hypothetical illustration. Mr. X. has a sore throat. He buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin. 2
By 1947, the first cases of antibiotic resistance were reported. How did Dr. Fleming so confidently predict this development? He understood homeostasis. Exposure causes resistance. A biological system that becomes disturbed tries to go back to its original state. As we use an antibiotic more and more, organisms resistant to it are naturally selected to survive and reproduce. Eventually, these resistant organisms dominate, and the antibiotic becomes useless.
To prevent the development of antibiotic resistance, we must severely curtail the use of antibiotics. Unfortunately, the knee-jerk reaction of many doctors to antibiotic resistance is to use more antibiotics to “overcome” the resistance—which backfires, since it only leads to more resistance.
Persistent, high-level use of antibiotics causes antibiotic resistance.
VIRAL RESISTANCE
WHAT ABOUT VIRAL resistance? How do we become resistant to viruses like diphtheria, measles or polio for instance? Before the development of vaccines, it was viral infection itself that caused resistance to further infection. If you became infected with measles virus as a child, you’d be protected from reinfection with measles for the rest of your life. Most (though not all) viruses work this way. Exposure causes resistance.
Vaccines work on exactly this principle. Edward Jenner, working in rural England, heard the common tale of milkmaids developing resistance to the fatal smallpox virus because they had contracted the mild cowpox virus. In 1796, he deliberately infected a young boy with cowpox and observed how he was subsequently protected from smallpox, a similar virus. Through being inoculated with a dead or weakened virus, we build up immunity without actually causing the full disease. In other words, viruses cause viral resistance. Higher doses, usually in the form of repeated vaccinations, cause more resistance.
DRUG RESISTANCE
WHEN COCAINE IS taken for the first time, there is an intense reaction—the “high.” With each subsequent use of the drug, the high becomes less intense. Sometimes users start to take larger and larger doses to achieve the same high. Through exposure to the drug, the body develops resistance to its effects—a condition called tolerance. People can build up tolerance to narcotics, marijuana, nicotine, caffeine, alcohol, benzodiazepines and nitroglycerin.
The mechanism of drug resistance is well known. To produce a desired effect, drugs, like hormones, are like keys that fit into the locks of the receptors on the cell surface. Morphine, for example, acts upon opioid receptors to provide pain relief. When there is a prolonged and excessive exposure to drugs, the body reacts by decreasing the number of receptors. Once again, the fundamental biological principle of homeostasis is at work here. If there is too much stimulation, the cell receptors are down-regulated, and the keys don’t fit into the locks as well. The biological system returns closer to its original state. In other words, drugs cause drug resistance.
VICIOUS CYCLES
THE AUTOMATIC RESPONSE to the development of resistance is to increase the dosage. For example, in the case of antibiotic resistance, we respond by using more antibiotics. We use higher doses or newer drugs. The automatic response to drug resistance is to use more drugs. An alcoholic takes higher and higher doses of alcohol to beat the resistance, which temporarily “overcomes” the resistance.
However, this behavior is clearly self-defeating. Since resistance develops in response to high, persistent levels, raising the dose in fact raises resistance. If a person uses larger amounts of cocaine, he or she develops greater resistance. As more antibiotics are used, more antibiotic resistance develops. This cycle continues until we simply can’t go any higher.
And it’s a self-reinforcing cycle—a vicious cycle. Exposure leads to resistance. Resistance leads to higher exposure. And the cycle keeps going around. Using higher doses has a paradoxical effect. The effect of using more antibiotics is to make antibiotics less effective. The effect of u