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Insulin Resistance

By David Mendosa

Last Update: December 7, 2009

Jackie's cholesterol, triglyceride, and blood pressure levels are too high. She's overweight and a couch potato. Her best friends describe her as being apple shaped, although her doctor calls it abdominal obesity.

Her underlying problem that she is insulin resistant. That means the cells in her body aren't using the insulin produced by her pancreas well enough. But the beta cells in her pancreas are producing lots of insulin—enough of it to overcome her insulin resistance and escort the glucose from the food she eats to the cells that need it.

Insulin resistance is real and serious.

Jack has the same problems—but there's one big difference. He has diabetes.


Because his pancreas isn't producing enough insulin to overcome his body's resistance to it. Beta cells of the pancreas tend to wear out after years of trying to make up for the resistance the body has to the insulin that it needs.

Insulin resistance
What is known as the Insulin Resistance Syndrome or Syndrome X is a very common metabolic disorder that between 60 and 75 million Americans have, according to Gerald Reaven, M.D., in his new book Syndrome X: Overcoming the Silent Killer that can Give You a Heart Attack (Simon & Schuster, 2000). Dr. Reaven identified the risk factors that tend to go together to form what he dubbed Syndrome X back in 1988.

"I wrote this lay book because I was getting disgusted with all the diet books that were starting with my work and were twisting it in ways that were totally wrong," he told me. He has written more than 500 professional papers and books, but this is the first for a lay audience.

Dr. Reaven names many risk factors for Syndrome X, not all of which everyone with the syndrome has:

  • Impaired glucose tolerance
  • High insulin levels (hyperinsulinemia)
  • Elevated triglycerides (blood fat)
  • Low HDL "good" cholesterol
  • Slow clearance of fat from the blood (exaggerated postprandial lipemia)
  • Higher than normal LDL "bad" cholesterol
  • Smaller, more dense LDL "bad" cholesterol particles
  • Increased propensity of the blood to form clots
  • Decreased ability to dissolve blood clots
  • Elevated blood pressure
  • Obesity
  • Lack of physical activity
  • The wrong diet
  • Cigarette smoking

Reaven believes that Syndrome X causes half or more of all heart attacks. Still, there aren't any official statistics showing how many people have insulin resistance or how many heart attacks that it causes.

Support for the thesis that insulin resistance is a major cause of heart attacks comes from the American Heart Association in a 1996 report in its journal Circulation. The association calls it a "landmark study" of 1,397 subjects since it showed insulin resistance was as important a predictor of coronary artery disease as the traditional risk factors such as high blood pressure.

To fight against insulin resistance Reaven recommends a diet that is 15 percent protein, 40 percent fat (mostly unsaturated) and 45 percent carbohydrate. Others recommend a different diet, and still other experts focus on weight loss or increased exercise or oral medications to counteract it.

The term is unfortunate
While Reaven writes about Syndrome X, that term is an unfortunate choice. It obscures the underlying factor, insulin resistance. Furthermore, the term Syndrome X has been used since 1973 to describe certain patients with angina. We therefore prefer to talk about the insulin resistance syndrome.

Actually, even the word syndrome is suspect, Ian Godsland and John Stevenson argued in a 1995 issue of The Lancet. Better call it a tendency, they say. That's because the risk factors don't always appear together in everyone. Still, insulin resistance (however defined) is real and is a serious condition.

Not everyone who has diabetes also has insulin resistance. People with type 1 diabetes almost never have it, because their beta cells are producing no insulin for their bodies to resist. But just about everyone who has type 2 diabetes does.

Both together cause type 2
"Both insulin resistance and beta cell dysfunction are necessary for type 2 diabetes to appear, and both of them appear before the diagnosis of this disease," says Dr. Arturo Rolla, assistant clinical professor of medicine at Harvard Medical School and Tufts University School of Medicine. He is also a staff member of the New England Deaconess Hospital. "If you have one problem but not the other, then you do not have type 2 diabetes."

Your beta cells in your pancreas are in areas called the Islets of Langerhans. Beta cells make and release insulin, which is a hormone that controls the level of glucose (a type of sugar) in the blood. With insulin resistance the beta cells of your pancreas have to pump out a lot of insulin to compensate for it. When the pancreas can no longer pump out enough insulin you get diabetes.

We have know the difference between those who have insulin resistance and those who don't since 1936. In his Lancet article H.P. Himsworth divided people with diabetes into insulin-sensitive and insulin-insensitive types, now called type 1 and type 2.

What comes first?
What comes first, the insulin resistance or beta cell dysfunction? Although it seems logical that years of pumping out lots of insulin because of insulin resistance would lead to beta cell dysfunction, nobody knows for sure. It is clear, however, that insulin resistance precedes type 2 diabetes.

Unlike blood pressure, glucose, or cholesterol, it's hard to measure insulin resistance. Something called the euglycemic insulin clamp and the minimal model analysis are the only two methods that provide a true measure of insulin resistance. Both methods are complex in one way or another. Neither is suitable for routine clinical use. This is probably why your doctor doesn't talk to you about insulin resistance.

If you have type 2 diabetes, it's a safe assumption that you have insulin resistance even without measuring it. If you have many of the risk factors of the insulin resistance syndrome without having diabetes, it's also safe to assume that you have insulin resistance.

Your insulin resistance may be in your genes. The indication of a genetic basis comes from studies of identical twins. Different rates of insulin resistance and resulting type 2 diabetes in different ethnic groups also suggest a genetic basis.

But insulin resistance is also something you can acquire. No one knows if obesity causes insulin resistance, or if insulin resistance causes obesity, or if they develop independently. We do know that insulin resistance is aggravated by obesity—particularly that type where your weight collects around your middle as in an apple. Physical inactivity also aggravates it. Even certain drugs that fight against the action of insulin are implicated. The experts no longer think that aging alone is a factor.

Why so common?
How could something as bad for us as insulin resistance become so common? Researchers have proposed several theories.

James Neel was looking at type 2 diabetes rather than the underlying insulin resistance in 1962 when he kicked off the debate in his article in the American Journal of Human Genetics. His hypothesis, that people with type 2 diabetes have a "thrifty" gene to cope with cycles of feast and famine, is practically taken for granted today.

"Famine, which had long been a recurrent condition, gave way to permanent plenty, and so the Pima's Ă«thrifty' genes, once an advantage, were now a liability," writes Malcolm Gladwell in his 1998 New Yorker article on "The Pima Paradox." The Pima are the Native American people living in Arizona whom he calls the most obese in the world. Half of all the Pimas over 35 have diabetes. Before the Pimas began to eat like other Americans, their high-fiber, low-fat diet with ample protein kept diabetes—but probably not insulin resistance—at bay.

But why should Westernization, like that affecting the Pima, lead to an explosion of diabetes? In spite of being no less subject to repeated famines than other people, Europeans have the lowest rates.

The carnivore connection
Two Australian professors, J.C. Brand-Miller and Stephen Colagiuri, have proposed a "carnivore connection" hypothesis that seems better at explaining the puzzle. Writing in Diabetologia in 1994 and the World Review of Nutrition and Dietetics last year, they propose that insulin resistance evolved to provide advantages to populations adapted to a high meat, low plant food (low carbohydrate) diet. With this diet, insulin resistance would not have caused high levels of circulating insulin.

Their thesis is that dietary carbohydrate plays a critical role in causing insulin resistance. Our primate ancestors ate a high-carbohydrate diet, and the brain and reproductive tissues evolved a specific requirement for glucose as a source of fuel. But the Ice Ages that dominated the last two million years of human evolution brought a low-carbohydrate, high-protein diet. Certain metabolic adaptations were therefore necessary to accommodate the low glucose intake.

Europeans may have a low incidence of insulin resistance and diabetes because they were among the first to adopt agriculture and their diet has been high in carbohydrate for 10,000 years. The selection pressure for insulin resistance (i.e., a low-carbohydrate diet) was therefore relaxed much sooner among Europeans than in other populations. Hence the prevalence of genes producing insulin resistance should be lower in the European population and any other group exposed to high-carbohydrate intake for a sufficiently long period of time.

Is low carb better?
Does all this mean that we should reduce our carbohydrate load? It certainly sounds like Brand-Miller and Colagiuri are recommending that. Yet their recent book on the glycemic index, The Glucose Revolution (Marlowe & Company, 1999), recommends a high carbohydrate diet.

So I asked her how she reconciled what appeared to be differing conclusions. "You are correct in picking up a leaning [in the articles on the carnivore connection] to low carbohydrate/high protein diets," she replied. "The trouble is we don't have much to go on yet. We need to see a lot more studies in both diabetic and non-diabetic subjects of all ethnic persuasions before we can recommend them."

The Diabetes Prevention Program
You will remember Jackie above who has insulin resistance that hasn't—yet—developed into diabetes. But it is clear that insulin resistance is often a dangerous precursor to diabetes. Right now a study called the Diabetes Prevention Program is under way to see which treatment for insulin resistance may help her prevent or delay the onset of diabetes. These treatments include diet, exercise, and medication. The DPP, however, won't be finished until 2002.

Jack's insulin resistance and beta cell dysfunction means that he has type 2 diabetes. The best way to treat his diabetes and underlying insulin resistance is just the same as what the Diabetes Prevention Program is testing.

Although you can't do much yet to change your genes, you can change your lifestyle factors that affect insulin resistance. Since insulin resistance is one of the underlying causes of diabetes, it shouldn't be a big surprise that the best treatment for it is very much like that generally recommended for diabetes itself.

The treatment is a three-pronged attack, which manages the symptoms of insulin resistance, including lifestyle changes that result in improvements in cholesterol, triglyceride, and blood pressure levels. The first two prongs are diet and exercise and the third are some new medications that attack insulin resistance at the source.

Further articles in this series will explore these three treatments more fully. 

I wrote this article in July 2000. An edited version of it appeared at, August 2000.


The National Institute of Diabetes and Digestive and Kidney Diseases announced August 8, 2001, that it had terminated the Diabetes Prevention Program one year early, because the results were already clear. The DPP was a major clinical trial comparing diet and exercise to treatment with metformin in 3,234 people with impaired glucose tolerance, a condition that often precedes diabetes. The study had originally four groups or "arms." One was based on intensive lifestyle changes with the aim of reducing weight by 7 percent through a low-fat diet and exercising for 150 minutes a week. The second was treatment with 850 mg twice a day of the drug metformin (Glucophage). They compared the success of these groups against the third group, which took placebo pills. The fourth arm, treatment with the drug troglitazone (Rezulin) combined with standard diet and exercise recommendations, was terminated in June 1998, because of its liver toxicity. Rosiglitazone (Avandia) and (pioglitazone) Actos, two leading drugs for the reduction of insulin resistance, were not available when the study started and were therefore not included. The diet and exercise group reduced their risk of getting type 2 diabetes by 58 percent. The group treated with metformin reduced their risk of getting type 2 diabetes by 31 percent. See

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