Insulin precursor linked with increased stroke risk; may represent new risk factor

November 29, 2000

DALLAS, Dec. 1 - Researchers may have identified a new marker to spot individuals at risk of a first stroke, according to a study reported in the December issue of Stroke: Journal of the American Heart Association.

The substance, proinsulin, turns into insulin under the right conditions. Insulin is a hormone that helps the body use glucose and other energy sources. In this Swedish study, non-diabetic people with high levels of proinsulin had a sharply increased risk of first-time stroke - especially women.

"High proinsulin concentration more than tripled the overall risk for first-ever stroke after adjusting for such risk factors as total cholesterol, high blood pressure, smoking, body mass index and insulin levels. And the risk for women was even more pronounced," says Bernt Lindahl, M.D., Ph.D., medical director of the Behavioral Medicine Clinic in the department of public health and clinical medicine, University Hospital of Northern Sweden.

The study found that non-diabetic men with the highest levels of proinsulin have more than a two-fold higher risk of stroke compared to men with the lowest levels. But for non-diabetic women the risk among those with the highest proinsulin levels is more than four times greater than for women with the lowest levels.

In women with both the highest diastolic blood pressure (the lower number in a blood pressure reading that represents the pressure between heart beats) and the highest levels of proinsulin, the risk of stroke jumps to nearly 20 times that of women in the study's lowest groups in both these categories, Lindahl adds.

"In the study, the diastolic blood pressure seems to be a stronger risk factor than the systolic blood pressure - the higher number that represents the pressure during the heartbeat," he says.

Lindahl describes proinsulin as a "not fully matured" form of insulin, a chemical substance produced by the pancreas to control the amount of sugar in the blood.

"The conversion of proinsulin to insulin occurs in several steps, mainly in the secretory granules in the beta cells of the pancreas," explains Lindahl. "The ratio of proinsulin to insulin in the blood stream is frequently increased in diabetes patients, possibly because high blood levels of glucose induce increased insulin release from the beta cells and speed up the conversion of proinsulin. This, in turn, causes increased levels in the blood stream."

The mechanisms by which proinsulin and possibly insulin itself may contribute to the development of first stroke are unclear, Lindahl notes. One hypothesis is that high proinsulin levels act as a marker for an underlying metabolic disturbance.

It has already been shown, in both diabetics and nondiabetics, that proinsulin has a stronger association than insulin to several cardiovascular risk factors, including high triglycerides, low levels of HDL or "good" cholesterol, high blood pressure and impaired glucose tolerance, he says.

No simple blood test suitable for measuring levels of proinsulin in large populations is currently available, Lindahl says. The test now used is highly technical, and although it could be performed in most hospitals, it remains largely confined to research projects.

There is also no "quick-fix" treatment for patients with high proinsulin levels. "Today, long-term lifestyle behaviors are the method of choice," Lindahl says. "But much research is being done to develop drugs that may decrease the demand on the beta cells by increasing the insulin sensitivity in muscle, fat and liver cells, in turn reducing levels of the insulin precursor."

In the future, proinsulin might be used as one risk indicator, which, when combined with other indicators, may help identify persons at increased risk of cardiovascular disease and/or type 2 diabetes. "If we can find these individuals, we can delay or prevent the occurrence of these diseases through lifestyle or pharmacological intervention," Lindahl emphasized. "But more research is needed before we can say that proinsulin measurements should be routinely used to identify high-risk patients."

Other researchers participating in the Swedish study include Bo Dinesen, M.Sc.; Mats Eliasson, M.D., Ph.D.; Michael Røder, M.D.; Göran Hallmans, M.D., Ph.D.; and Birgitta Stegmayr, Ph.D.
NR00-1219 (Stroke/Lindahl)

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