Diabetes drugs have made a big difference to George Marincin and Kristin Chapman. For a few weeks last year, Marincin, 77, from Tacoma, Wash., took artificial insulin, the hormone that's deficient in diabetics. And every day Chapman downs doses of Glucophage, a drug that helps the 38-year-old from Atlanta to better control the hormone.

But neither Marincin nor Chapman has diabetes.

What Marincin does have is Alzheimer's disease. He took insulin to test the idea that low levels might be linked to memory problems. "I did wonder how insulin could help George because he's not diabetic," says his wife, Mabel. "But it has. It's wonderful." Her husband has regained his sense of humor and can even complete simple tasks again like making a cup of tea, she says. Last month his doctors reported in the Archives of Neurology that other patients also seemed to benefit.

Chapman was just as surprised that adjusting insulin levels could help her. She has polycystic ovary syndrome, which causes infertility and dramatically raises her risk for heart disease. But her problem wasn't too little insulin but too much, which prevents ovulation. After seven years of struggling to conceive, she started taking Glucophage and was pregnant in a month. "It's mind boggling, isn't it?" she says. Now the happy mother of two kids, she'll stay on the drug for the rest of her life to keep her high insulin in check.

Insulin problems--too much or too little--go far, far beyond diabetes. The condition is called insulin resistance and, in addition to the ailments dogging Chapman and Marincin, doctors are now discovering it is linked to heart attacks, strokes, and several kinds of cancer and may affect 1 in 3 American adults. These findings have alarmed many specialists. "Insulin resistance is very common, and it's associated with the biggest killers," says endocrinologist Ronald Kahn, director of the Joslin Diabetes Center at Harvard University. "If we don't start paying attention to this now, we're all going to be paying a huge price for this condition." Physician David Katz, director of the Prevention Research Center at Yale Medical School, adds that "we're just beginning to understand that insulin throws a lot of big switches in the body. Is insulin the master control of all disease? I don't know, but it's certainly a candidate for that role."

Insulin's main job is to escort sugar out of the blood and into muscle and fat cells. But sometimes those cells resist letting it in. So the pancreas, which makes insulin, tries to crank out even more. If it can't, blood sugar climbs to dangerous levels and the result is Type II diabetes. More often, however, the pancreas does make more insulin. The extra hormone may restore blood sugar to normal, but it overwhelms the rest of the body. That spells trouble, because insulin is more than just a sugar ferry. It tells the kidneys, for example, to hold on to salt. And more salt means hypertension. It tells cancer cells to grow, and that can mean a tumor.

Fortunately, doctors are starting to devise new ways to treat insulin resistance--which is sometimes called "metabolic syndrome" --with drugs and lifestyle changes. They are still working out all the connections, but already they have a list of some of the leading insulin-related illnesses:

Cancer

Insulin stimulates cell growth, and unfortunately cancer cells have six to 10 times the number of insulin receptors--molecules that grab on to the hormone--as do normal cells. So if extra hormone hits a pre-existing cancer cell, it makes a bad thing much, much worse. "For cancer, insulin is like pouring gasoline on a fire," says Edward Giovannucci, who studies the epidemiology of colon cancer at the Harvard School of Public Health.

Colon, breast, endometrial, pancreatic, and prostate cancers seem especially responsive. "We think breast cancer cells may have very special kinds of receptors, fetal insulin receptors, that are ultrasensitive to insulin," says Pamela Goodwin, director of the Marvelle Koffler Breast Center at Mount Sinai Hospital in Toronto. Insulin may also influence estrogen, another hormone that can trigger tumor growth. "So if you turn on one hormone, you turn on the other," Goodwin says. She is currently testing Glucophage to see if it can lower insulin levels in breast cancer survivors and plans to see if this affects cancer recurrence.

Cardiovascular Disease

High levels of insulin in the blood damage the lining of arteries, increase bad blood fats such as triglycerides and LDL cholesterol, and clump blood cells together so they are more likely to block up vessels. These observations prompted Gerald Reaven, the Stanford endocrinologist who first described insulin resistance in the 1980s, to finger the condition for heart attacks, strokes, and cases of high blood pressure.  Other research has come to back him up. A major study by Finnish researchers in the journal Circulation followed almost 1,000 men for 22 years and found insulin levels alone were the most powerful predictors of heart attack risk, especially in younger men. They were more powerful than obesity levels and physical inactivity, for example. Men with the highest insulin levels had more than three times the heart attack risk of those with the lowest. [Obese people are much more likely to have high insulin levels—jk]

The concept does have its critics. Last week in the journal Diabetes Care , Richard Kahn, chief scientific and medical officer for the American Diabetes Association, wrote an article questioning whether the idea of insulin resistance is truly useful, particularly when it comes to diagnosing and helping heart patients. Just calling something by a new name, he argues, doesn't change the recommended therapies. "I don't see the value . . . especially when the treatments are the same," says Kahn. He points out that if patients have high cholesterol, they're going to get cholesterol-lowering drugs and advice on diet and exercise, whether or not insulin resistance is the root cause.

But other experts see value in understanding insulin's role in the clustering of cardiovascular risk factors, particularly if it points the way toward new treatments. It's already doing that for stroke, for it's here that one new treatment is being tested. This spring the

National Institutes of Health began a study at more than 60 research sites to see if the drug Actos, an insulin sensitizer, can reduce stroke recurrence in certain patients.

Ovary Disease

According to the American Association of Clinical Endocrinologists, polycystic ovary syndrome affects 1 in 10 women and is the leading cause of infertility in the United States. High levels of insulin trigger excess production of other hormones by the ovaries, disrupting regular egg growth and menstrual cycles and preventing pregnancy. Some of these overproduced hormones, or androgens, can also cause male-pattern hair growth on the face and some other unpleasant appearance changes. Basically, says Mark Perloe, an Atlanta endocrinologist and polycystic ovary syndrome specialist, "insulin is driving the ovary crazy."

Doctors now treat this ovary syndrome with insulin-sensitizing medications like those taken by Chapman, and also recommend weight loss, which lowers insulin levels. Treatment is important even beyond fertility problems, because untreated women with the polycystic syndrome have more than seven times the risk of heart disease and three times the risk of diabetes of women without it.

Alzheimer's

Cells in the brain's memory and learning centers have a lot of insulin receptors. A quick spike in insulin improves memory and performance; take insulin away, and brain function begins to decline. But paradoxically, more insulin in the blood--insulin resistance--means less in the brain. One leading theory: Insulin's corrosive effects on blood vessel linings gums up tiny portals in the vessels that supply the brain, making it harder for the hormone to bring in sugar. Ultimately, this starves brain cells, suggests researcher Suzanne Craft of Veterans Administration Puget Sound Health Care System. That could set the stage for some cases of Alzheimer's, Parkinson's, and Huntington's diseases. Insulin also seems to clear away some beta-amyloid, a substance long implicated in Alzheimer's damage, so less of it could cause problems.

There are, of course, many theories about Alzheimer's, and this is far from the final word. But whatever the reason for the disease, there is preliminary evidence that getting insulin to the brains of Alzheimer's patients improves symptoms. In Craft's recent study, a small group of Alzheimer's patients, including Marincin, inhaled insulin. (Inhalation provides more of the hormone to the brain.) Compared with a group that only inhaled saline solution, these patients better recalled stories and lists. It's not known, however, how long these improvements last. Craft is now testing the insulin sensitizer Avandia in people with Alzheimer's to see if it might slow down the disease.

The tests of all these drugs may sound good, but they are far from the only treatment--or the best--for insulin resistance. There's a lot of hope to be found around the dinner table. Most people with resistance can actually undo it by losing as little as 5 to 20 pounds. The best eating plans, say experts, offer lots of soluble fiber, the kind found in berries and beans and whole oats, which seems to indirectly diminish resistance, as well as lean proteins like fish. Saturated fats may cause insulin to spike, so look for foods with healthy fats like nuts and avocados. But enjoy them in moderation.

Weight loss is important because all the risks for all the diseases associated with insulin resistance are multiplied by obesity. That spare tire many of us carry around the middle packs the liver in fat, and the liver responds by tossing high levels of free fatty acids into the blood. These fats seem to block insulin from docking with its receptors on cells, increasing the risk of starting the resistance syndrome.

Regular exercise also helps muscles better use insulin, so in addition to her medication, Kristin Chapman works out four times a week. She also gets her heart checked every year, and has started getting regular mammograms early, at age 35. If insulin does indeed turn on many diseases, she plans on doing her best not to throw the switch.