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Insulin Resistance

By David Mendosa

Last Update: January 31, 2002

Although we have known about insulin resistance for a long time, it is only recently that most of us have become interested in it. I think that there are two reasons for our greater concern.

‘I call type 2 diabetes a two-hit disease.’

For 66 years we have known the difference between people who have insulin resistance and those who don't. In his January 1936 Lancet article Sir Harold Himsworth, M.D., divided people with diabetes into insulin-sensitive and insulin-insensitive types, now called type 1 and type 2. People with type 1 diabetes—those whose beta cells produce essentially no insulin—are rarely insulin resistant.

It took the work of Gerald Reaven, M.D., to kick off the current wave of interest in insulin resistance. An endocrinologist who taught at Stanford University from 1959 to 1995 and who since then has been senior vice president for research for Shaman Pharmaceuticals in South San Francisco, Dr. Reaven took us much closer to understanding the condition in a 1988 lecture. His Banting Lecture on the "Role of Insulin Resistance in Human Disease" in the American Diabetes Association's professional journal Diabetes was the first to link insulin resistance with related variables including high cholesterol and high blood pressure as a cluster of risk factors for heart disease. It was in this article that he bestowed the name "Syndrome X" to these variables.

Four or five non-professional books about insulin resistance and Syndrome X have appeared in the last couple of years, bringing these concepts to a much broader audience. The best of the bunch is Dr. Reaven's Syndrome X (Simon & Schuster, 2000).

When I interviewed him at that time he told me that it was his first lay book after publishing more than 500 articles in scientific journals. He wrote the book, he said because he was "disgusted with all the...books that were starting with my work and were twisting it in ways that were totally wrong."

Dr. Reaven has an online introduction to insulin resistance. While people with type 2 diabetes have insulin resistance, 20 to 25 percent of the U.S. population—about 70 million people—are also insulin resistant. This could make insulin resistance the most common cause of chronic disease, says epidemiologist Rodolfo Valdez of the U.S. Centers for Disease Control and Prevention.

The perhaps 20 million Americans with impaired glucose tolerance who haven't (yet) got diabetes are among those who are insulin resistant. The recently completed Diabetes Prevention Program, which studied people with IGT, showed that diet, exercise, and drugs such as Glucophage can delay if not prevent diabetes.

But if insulin resistance goes on for so long that your pancreas can't pump out enough insulin to make up for your body's impaired sensitivity to it, type 2 diabetes does result. Scientists at the National Institutes of Health proposed in a 1991 American Journal of Medicine article what they call a "two-step model" for the development of type 2 diabetes—first insulin resistance and then beta-cell dysfunction. That's why I call type 2 diabetes a "two-hit" disease.

Besides the work of Dr. Reaven, the second reason for our heightened interest in insulin resistance is that we now have the tools to deal with it. These tools are drugs, formally known as oral hypoglycemic agents.

For 40 years between 1955, when Orinase (tolbutamide) became available, and 1995, we had a Hobson's choice of oral drugs. We could use a sulfonylurea or nothing.

Sulfonylureas help the body release more insulin. But they don't do anything to counter insulin resistance.

In 1995 the first of a new class of drugs called biguanides became available in the United States after a lengthy Food and Drug Administration approval process. Glucophage (metformin hydrochloride) was the first drug introduced that reduces insulin resistance. The manufacturer, Bristol-Myers Squibb Company, is, however, strangely reluctant to make that precise claim. Its prescribing information says only that it "improves insulin sensitivity," which sounds to me like the other side of the same coin.

More recently the FDA approved yet another class of drugs, the thiazolidinediones, that work to overcome insulin resistance by making the body's cells more sensitive to insulin. Two drugs in this class are currently available, Avandia (rosiglitazone maleate) and Actos (pioglitazone hydrochloride).

With this knowledge and these tools we have seen a recent explosion of interest in insulin resistance. A Google search for "insulin resistance" returns more than 56,000 pages. A Yahoo group with about 200 members focuses specifically on it. And the topic comes up again and again on other mailing lists. We have begun to understand insulin resistance. Perhaps that understanding will someday soon lead to a cure. 

The American Diabetes Association originally published this article on its Web site as one of my “About the Internet” columns.

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