Hidden heart hazards; do high blood insulin levels foretell heart disease?

Hidden Heart Hazards

Controversial findings from several research teams suggest that insulin resistance -- a disorder in which cells respond sluggishly to insulin -- forms the lethal core of a process that can lead to clogged arteries. The research connects high levels of insulin in the bloodstream to heart disease. If confirmed, it will give physicians a powerful new predictor of heart disease risk and could force them to reexamine dietary prescriptions for improving heart health.

By some estimates, up to 25 percent of trim people in the United States inherit or acquire an inefficient response to insulin, the pancreas-secreted hormone that directs cells to take up glucose. These people are not diabetic, but their lethargic response to insulin means the pancreas must churn out more of the hormone to keep blood sugar levels normal. Most diabetes specialists believe people with insulin resistance face a risk of developing Type II, or non-insulindepdent, diabetes when the pancreas exhausts its ability to crank out enough hormone to meet the body's needs.

Not everyone with insulin resistance develops Type II diabetes, which generally strikes after age 40. Yet even in those who escape it, some researchers now believe that a long-standing elevation of insulin in the blood silently damages the cardiovascular system by an unknown process that results in the buildup of fatty deposits on artery walls.

That theory has sobering implications for outwardly healthy people with insulin resistance as well as for the 10 million Type II diabetics in the United States, most of whom are insulin resistant.

"Resistance to insulin-stimulated glucose uptake is involved in the development of coronary artery disease," contends Gerald M. Reaven of Stanford University School of Medicine. "Although this concept may seem outlandish at first blush, the notion is consistent with available experimental data."

Reaven's 20 years of research on insulin resistance led him in 1988 to coin the term "syndrome X," describing seemingly healthy people who have insulin resistance and display a cluster of coronary risk factors, including high blood pressure, elevated triglycerides (a form of lipid, or fat, in the bloodstream) and decreased high-density lipoproteins, or HDLs -- the beneficial transport molecules that carry cholesterol from the bloodstream to the liver for excretion (SN: 9/9/89, p. 171).

Insulin resistance may explain why Type II diabetics are two to four times as likely as nondiabetics to develop heart disease, running a coronary risk comparable to that of insulin-dependent, Type I diabetics without kidney disease. But Reaven's theory of syndrome X goes well beyond diabetics in stating that trim, outwardly healthy people with a defective insulin response also face a greater-than-average risk of heart disease -- a notion many diabetes specialists view with cautious skepticism.

"It's an interesting idea, but [syndrome X] is not proven by the data," comments diabetes researcher Daniel W. Foster of the University of Texas Southwestern Medical Center in Dallas. Adds cholesterol researcher Scott M. Grundy, also at Southwestern Medical Center: "Syndrome X might be syndrome zero."

Nonetheless, the notion is attracting considerable attention as new scientific reports from around the world support the link between insulin resistance and coronary artery disease.

British researchs, for instance, have long puzzled over the paradox posed by South Asian immigrants, who suffer extraordinarily high heart disease rates despite their relatively healthy risk profiles. "What we are finding in South Asians is precisely what Reaven describes as syndrome X," reports Paul M. McKeigue of the University College and Middlesex Hospital Medical School in London. McKeigue presented early research results last June at the International Conference on Preventive Cardiology in Washington, D.C.

People from India and Pakistan generally shun the British penchant for clotted cream, opting for diets low in saturated fat. Their total blood cholesterol levels lie well below the British national average of 232 milligrams per deciliter (mg/dl), yet their cardiac death rate exceeds the British average by 50 percent.

"We were looking for some explanation, something that could explain why the rates of coronary heart disease were so high,c McKeigue says. His preliminary study of 288 South Asian and 373 white West London factory workers suggests some South Asians inherit a flawed insulin response that leads to several cardiovascular risk factors.

Scientists can't test for insulin resistance directly, so they look for clues to the disorder, such as high blood insulin levels. After an overnight fast, the South Asians had blood insulin levels averaging 20 percent higher than those of white subjects, McKeigue says. Moreover, when the researchers measured insulin values two hours after administering a blood glucose test--a standard sugard dose given in liquid form to trigger insulin release--the South Asians showed levels 66 percent higher than those of the white factory workers.

McKeigue's team found another possible sign that South Asians inherit insulin resistance: potbellies. Evidence from several countries suggests potbellies can reflect the body's poor response to insulin. On average, South Asians in the study had waist-to-hip ratios 1 standard deviation higher than those of the whites.

The lipid profile emerging from this study seems to fit with Reaven's description of syndrome X: South Asians had blood triglyceride levels 17 percent higher, and HDL cholesterol levels 10 percent lower, than their white counterparts. In addition, 15 percent of the South Asians, compared with 7 percent of the whites, had abnormal electrocardiograms indicating coronary artery disease.

Moreover, the South Asians werethree times as likely to have Type II diabetes, McKeigue says--a finding consistent with the notion that some people with insulin resistance go on to develop overt, Type II diabetes.

Perhaps the most compelling evidence for syndrome X comes from a study of Italians working in a pasta factory. Reaven teamed up with Ivana Zavaroni and her colleagues at Parma (Italy) University to study 247 apparently healthy, nondiabetic workers, finding 32 nonobese people with insulin levels that were 2 standard deviations higher than the group mean. They matched these high-insulin people with 32 controls who had insulin levels within 1 standard deviation of the group mean.

The researchers found that the high-insulin group mirrored Reaven's pattern of risk characteristics. Triglyceride values in this group were significantly higher than those of controls (153 vs. 110 mg/dl), while HDL cholesterol levels were lower (47 vs. 55 mg/dl). High-insulin individuals also had higher blood pressure readings than controls.

"We conclude that healthy persons with [high blood insulin levels] have an increase in risk factors for coronary artery disease, as compared with a well-matched group of healthy subjects with normal inslin levels,c the researchers write in the March 16 NEW ENGLAND JOURNAL OF MEDICINE.

Last June, at the annual meeting of the American Diabetes Association in Detroit, French researchers reported that long-standing elevations in blood insulin levels do seem to predict a greater threat of fatal heart attack. Annick Fontbonne and her colleagues at the French National Institute of Health and Medical Research in Paris found a link between blood insulin values and heart disease mortality in a 15-year study of 7,038 Paris policemen, whose ages ranged from 43 to 54 at the study's outset.

"Our studies indicate that the earliest marker of a higher risk of coronary heart disease mortality is an elevation of plasma insulin level," Fontbonne says. When the researchers looked back at their records, they found that the 169 men who died of heart disease during the project had entered the study with fasting insulin values averaging about 20 percent higher than those of survivors. Insulin values measured two hours after a glucose test were 13 percent higher for the 169 than for the survivors, Fontbonne says.

U.S. research also implicates insulin resistance in the development of some forms of coronary artery disease. At the University of Pittsburgh School of Medicine, a new study of 489 healthy, white, premenopausal women aged 42 to 52 shows an increasing risk of heart disease as blood levels of insulin rise. Women with the highest blood insulin levels proved the most likely to have high blood pressure, elevated triglycerides and decreased HDL cholesterol values.

"The finding that insulin, independent of obesity, is related to coronary heart disease risk factors is an important development,c study director Rena R. Wing told SCIENCE NEWS. She stresses that many of these women appeared quite healthy. The average study participant weighed 145 pounds and had a total blood cholesterol count of 185 mg/dl, a level considered desirable by the federal National Cholesterol Education Program. Wing and her colleagues, who describe their work in the July/August ARTERIOSCLEROSIS, plan to study the same women asthey go through menopause to see whether early signs of coronary disease will lead to higher heart disease mortality rates.

Despite these intriguing findings, the mechanism by which insulin resistance might cause heart disease remains a mystery. Some scientists speculate that high insulin levels may directly damage the artery wall, leading to a lipid buildup that narrows the vessel. Alternatively, insulin's regulation of lipid metabolism may alter the triglycerides or HDL cholesterol in the blood, a process that could lead to artery disease, Reaven notes.

Scientists have yet to unravel the complicated relationship between the genetic and environmental factors underlying insulin resistance and, by inference, syndrome X. A number of scientific reports suggest insulin resistance is inherited, but researchers don't know whether one gene or several control its development. And while scientists do know that obesity often impairs insulin response, they don't know whether other factors might also trigger insulin resistance.

"The most likely possibility is that syndrome X is genetically determined, but the genetic defct remains hidden without some environmental precipitant -- probably one involving diet," writes Foster, of the University of Texas, in an editorial accompanying Reaven and Zavaroni's March 16 research report. "Thus, if insulin resistance is pathogenetic, it is more likely an accomplice than the sole killer."

If more extensive research verifies syndrome X, clinicians of the future might screen patients for insulinresistance by monitoring blood insulin levels or by looking for potbellies, Reaven and McKeigue say. Once identified, people with insulin resistance might lower their coronary risk by losing weight or boosting their physical activity, since both measures can help the body use insulin more efficiently, Reaven says.

For Type II diabetics, the theory's implications seem doubly dangerous. "If mild elevations of insulin are harmful, that's a fairly worrisome thing for people who treat diabetes, because diabetics have excess insulin around all the time," comments Foster. Most clinicians focus on controlling diabetics' blood sugar levels and haven't worried much about the heart dangers caused by excess insulin, he says.

Reaven, Fontbonne and other proponents of the theory believe high blood insulin indicates insulin resistance and triggers the process leading to heart disease. But skeptics say high blood insulin could simply flag some as-yet-unknown process that damages heart arteries. They contend insulin resistance itself might play no role, or only a minor role, in the development of heart disease.

Reaven agrees the theory requires further study, but he remains convinced that the experimental evidence strongly suggests that insulin resistance causes heart disease in some people.

"People don't like to have the dogma questioned," he says, "but I've been doing that for 20 years."