Type 2 Diabetes in Women

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If you're over age 40 and overweight, and you don't get enough exercise, you are at risk for type 2 diabetes, the most common form of this disease. That has particularly ominous implications for women, because they not only are more likely to develop the disease than men are, they also are disproportionately affected by its complications. Women with diabetes are seven times more likely to die of heart disease than nondiabetic women. For diabetic men, the equivalent increase in risk -while serious enough - is only two- to three-fold. Diabetic women also have a significantly higher incidence of congestive heart failure compared with diabetic men. When it comes to heart disease risk, diabetes completely erases a woman's premenopausal advantage over men.

Researchers do not yet know all the mechanisms involved in type 2 diabetes. It is far more complicated than was once thought, involving many genes, organs, and metabolic functions. Fortunately, treatment options have grown along with our recognition of its complexity. The best news in recent years is how effective diet and exercise are in preventing diabetes and reducing its severity.

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DIABETES BASICS
Diabetes develops when glucose can't get into cells and instead builds up in the bloodstream. Our bodies need glucose - a simple form of sugar that supplies energy to the cells - in order to function properly. The main source of glucose is food, mostly carbohydrates that break down to sugar in the intestine and cause blood glucose levels to rise. In response, the pancreas releases the hormone insulin, which directs glucose from the blood into the cells, either for immediate use or to be stored in fat and muscle. In so doing, insulin returns blood glucose levels to normal.

Type 1 diabetes, an autoimmune disorder that destroys the insulin-producing capacity of the pancreas, usually develops in childhood or adolescence. In type 1, the body cannot produce enough insulin to drive glucose into the cells, causing blood glucose levels to rise. Type 2 diabetes most commonly starts in adulthood. In this form of the disease, the pancreas makes plenty of insulin, but fat, muscle, and other cells resist the normal action of insulin - a condition called insulin resistance. This leads to elevated blood glucose levels (hyperglycemia). As part of the same process, the liver produces additional sugar, as well as triglyceride-rich lipoproteins, which raise LDL (bad) cholesterol and lower HDL (good) cholesterol. Blood pressure rises, and abdominal fat increases. These changes occur in both sexes, but particularly so in women.

Ninety percent of all diabetics have type 2 diabetes. Genetics, aging, and some medications can cause insulin resistance, but the main non-genetic factors are overweight and lack of exercise. Of the 800,000 Americans who will be diagnosed with type 2 diabetes this year, 90% will be overweight. How excess weight causes insulin resistance is unknown, but recent research suggests that fat cells secrete a hormone dubbed resistin that interferes with insulin action.

Insulin resistance alone is generally not enough to lead to clinical diabetes because the pancreas can compensate for a long time by pumping out more insulin. But eventually the pancreas becomes exhausted and cannot continue to produce high levels of insulin. As a result, glucose builds up in the blood and causes problems throughout the body. In the short term, diabetes can cause fatigue, nausea, frequent urination, increased thirst, and blurred vision. Uncontrolled, diabetes damages both large and small blood vessels, resulting in cardiovascular disease, blindness, kidney failure, and nerve disease.

WOMEN, DIABETES, AND HEART DISEASE
Women with diabetes tend to have cardiovascular risk factors that are more pronounced. For instance, the Strong Heart Study of cardiovascular disease in American Indians found that women with diabetes had greater increases in blood pressure and upper body obesity, higher levels of LDL cholesterol, and lower levels of HDL cholesterol than their male counterparts. Some researchers suspect that high blood glucose interferes with the heart-protective effects of estrogen. But how insulin resistance actually causes these malfunctions is not known.

According to new guidelines issued in May by the National Cholesterol Education Program (NCEP), women with diabetes are at as great a risk for heart attack as women who already have heart disease. Experts advise aggressively treating high cholesterol in such women with cholesterol-lowering drugs such as statins.

TREATING DIABETES: LIFESTYLE CHANGES REQUIRED
Weight loss - by way of exercise, diet, or both - is essential in treating type 2 diabetes. Losing 10 pounds can mean a return to normal blood sugar levels, even if you are significantly overweight. Weight loss lowers insulin resistance and helps your body use its insulin more efficiently.

For people with diabetes, staying active lowers the risk for cardiovascular disease, contributes to weight reduction, and helps use up glucose, which lowers blood glucose levels. And it increases insulin sensitivity, the opposite of insulin resistance. Exercise may also be the best way to prevent diabetes. The Harvard-based Nurses' Health Study and Physicians' Health Study have found, respectively, that women and men who exercise at least 5 times per week are about 40% less likely to develop diabetes than those who don't exercise.

Dietary control of diabetes centers on eating healthy meals and snacks on a regular schedule and shunning excess calories. Several studies have shown that fiber also helps. Research last year in the New England Journal of Medicine found that a high-fiber diet (50 grams per day) lowered blood sugar levels by 10%. That compares favorably with the effects of some currently available drugs.

While diet and exercise are the cornerstones of type 2 diabetes prevention and treatment, people with diabetes sometimes need medication as well.

TREATING DIABETES: MEDICATIONS
Until fairly recently, the only oral diabetes drugs in the United States were sulfonylureas, medications that drive down blood sugar levels by increasing insulin production. When they failed, insulin injections were required. The past five years have seen a big change. The number of medications has more than tripled and whole new classes of drugs have been introduced. Today's diabetes drugs address insulin resistance and production as well as high blood sugar levels. Doctors not only have a wider range of drugs to choose from, they also use them more aggressively.

If medications are inadequate, insulin injection is still the most effective therapy. Several companies are developing an inhaled form of insulin.

COMBINATION THERAPY
Traditionally, clinicians have used one treatment at a time for type 2 diabetes. If one therapy failed, another was substituted or added. But this approach succeeded in controlling blood sugar levels for only about a quarter of all patients. Now physicians are treating diabetes more effectively with multiple drugs in combination. This generally means lower doses of each individual drug and fewer side effects.

The most commonly used oral drug combination is metformin and a sulfonylurea, but other combinations are being tested. Last year, researchers at Tulane University reported that a combination of metformin and rosiglitazone was better than metformin alone in improving blood sugar control, insulin sensitivity, and pancreatic cell function. Even if insulin shots become necessary, use of an oral drug as well can mean lower insulin doses.

Some diabetes experts also recommend that medications be started immediately - in conjunction with diet and exercise - rather than waiting to see if lifestyle changes alone will control blood sugar levels.

For Women With Diabetes
Official guidelines for preventing cardiovascular disease in women recommend these targets for women with diabetes:

Fasting blood glucose = 80-120 mg/dL
Bedtime blood glucose = 100-140 mg/dL
Hb A1c (reflects fasting and post-meal blood glucose levels over the preceding two to three months) <7%
LDL <100 mg/dL
HDL = 60 mg/dL
Triglycerides <150 mg/dL
Sources: Mosca, L et al. "Guide to Preventive Cardiology in Women," Circulation (May 11, 1999): Vol. 99, pp. 2480-2484; "Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP)..." Journal of the American Medical Association (May 16, 2001): Vol. 285, pp. 2486-2509.

Lessons From the Nurses' Health Study
Over the course of 25 years, the Nurses' Health Study has identified several lifestyle factors related to diabetes risk.

Type-2 diabetes risk rises steadily with weight. Women with a body mass index (BMI) of 23-24.9 have triple the risk of leaner women. A BMI is 31 or more carries 16 times the risk.
Women who gain 12 or more pounds after the age of 17 are at higher risk of diabetes than women whose weight remains stable. The more weight gained, the higher the risk. Losing 12 or more pounds similarly lowers risk.
Type-2 diabetes risk rises with waist size, starting at 28.
A new book, Healthy Women, Healthy Lives: A Guide to Preventing Disease from the Landmark Nurses' Health Study, summarizes these and other findings from the Nurses Health Study. If you would like to view the table of contents for this book on our Web site, go to: www.health.harvard.edu/newsletters/womentoc.shtml.

MEDICATIONS FOR TYPE-2 DIABETES
Drugs Comment

Sulfonylureas Effectiveness declines over
* acetohexamide (Dymelor) years. Should not be taken
* chlorpropamide (Diabinese) by those allergic to sulfa
* glipizide (Glucotrol, drugs. Can cause hypoglycemia,
Glucotrol XL) rash. Tolbutamide may cause
* glyburide (DiaBeta, Glynase changes in taste.
PresTab, Micronase)
* glimepiride (Amaryl)
* tolazamide (Tolinase)
* tolbutamide (Orinase)

Biguanides
* metformin hydrochloride May lower cardiovascular
(Glucophage) disease risk. Can cause nausea,
diarrhea, flatulence.

Meglitinides
* nateglinide (Starlix) Less risk for hypoglycemia
* repaglinide (Prandin) than with sulfonylureas. May
be safer in older patients
and in those with kidney
failure.

Alpha-glucosidase inhibitors Moderates blood sugar
* miglitol (Glyset) surges after a meal. Can
* zacarbose (Precose) cause diarrhea, flatulence.

Thiazolidinediones Liver enzymes should be
* pioglitazone (Actos) monitored. Can cause anemia,
* rosiglitazone (Avandia) edema, weight gain. May make
birth control pills less
effective.

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