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Protein Linked to Insulin Resistance in Humans

Discovery could lead to targeted therapies for preventing type 2 diabetes

WEDNESDAY, June 14, 2006 (HealthDay News) -- Lowering blood levels of a protein found in higher quantities among those with insulin resistance might cut the risk of diabetes, metabolic syndrome and cardiovascular disease, a new study suggests.

The finding, reported in the June 15 issue of the New England Journal of Medicine, could lead to better screens for insulin resistance, a new test that could better assess the effects of diet and exercise programs on reducing diabetes risk, and new therapies targeted at lowering the levels of this molecule, known as retinol-binding protein 4 (RBP4).

"In this study, we have found a new molecule which seems to track very tightly with insulin resistance and the metabolic syndrome, which is a constellation of insulin resistance and other cardiovascular disease risk factors," said lead investigator Dr. Barbara Kahn, chief of the division of diabetes, endocrinology and metabolism at Beth Israel Deaconess Medical Center, and a professor of medicine at Harvard Medical School in Boston.

Kahn said the current study found an association between RBP4 and insulin resistance, but the researchers couldn't confirm whether or not RBP4 is simply a marker of insulin resistance or if it actually causes insulin resistance.

However, previous research done by Kahn's group on animals seems to suggest that RBP4 may play some role in the development of insulin resistance.

"In the animal studies from last year, we showed that elevating the levels of RBP4 can cause insulin resistance. Furthermore, preventing the usual rise in serum RBP4 levels seen in mice on a high-fat diet can markedly reduce their insulin resistance," she said.

RBP4 is normally used by the body to transport vitamin A in the blood, according to the study.

Nearly 21 million Americans suffer from diabetes, according to the American Diabetes Association. About 90 percent to 95 percent of those people have type 2 diabetes, and insulin resistance is often a precursor to the disease. Since the body's cells don't use insulin properly with insulin resistance, blood sugar rises and the pancreas continues to produce more and more insulin to try to lower the blood glucose level. Over time, however, the pancreas can't keep up with this demand and begins to lose its ability to produce insulin, resulting in diabetes.

Because the animal studies so closely linked RBP4 and insulin resistance, the researchers wanted to know if there was an association between this protein and insulin resistance in humans.

To assess the relationship in people, the researchers looked at blood samples from people from three different areas: California, Sweden and Germany. They chose three distinct groups of people -- the largest group included 60 volunteers.

The first group included lean people, obese people without diabetes and obese people with type 2 diabetes. The second group was made up of people who had normal glucose metabolism, impaired glucose metabolism or type 2 diabetes. The final group included non-obese people with a strong family history of type 2 diabetes.

In the first group, the lean study volunteers had the lowest levels of RBP4, with an average of 24 micrograms per milliliter (mcg/ml). For obese people without diabetes, the average was 39 mcg/ml, while the obese volunteers who had diabetes averaged 41 mcg/ml.

Those with insulin resistance had higher levels of RBP4 in the second group. The group with normal glucose tolerance had an average level of 26 mcg/ml, while those with impaired glucose tolerance had an average level of 60 mcg/ml. People with type 2 diabetes had an average of 63 mcg/ml.

The third group of people -- who weren't obese -- had an average level of 31 mcg/ml, which was higher than the lean subjects in the first group, indicating that their family history of the disease might be putting them at an increased risk of diabetes. That means that RBP4 might be able to be used as a screening test for those at high risk to measure who is more likely to develop diabetes.

Additionally, the researchers found that high levels of RBP4 were associated with a higher body mass index, elevated hip-to-waist ratio, higher triglyceride levels, decreased HDL cholesterol and increased blood pressure. All of these factors are part of metabolic syndrome, and suggest a greatly increased risk of heart disease.

Finally, the researchers had some of the participants exercise at a moderate pace three to four times a week for about 60 minutes at a time.

"A reasonable amount of exercise lowered RBP4. It was a protocol that many people could carry out," Kahn said.

"In people with insulin resistance, RBP4 is something that could be followed and could be used to motivate patients to make lifestyle changes. They could see how the levels of RBP4 are going down, and use this as an indication that the changes are working," she said. Kahn added, however, that the commercially available tests for RBP4 aren't yet sensitive enough to do this.

She said her team is interested in doing a study to see if lowering RBP4 levels would be helpful in people with diabetes. Because RBP4 is used for vitamin A metabolism, it couldn't be knocked out completely, Kahn said, but doctors would only need to reduce levels to normal.

"Clearly, this study demonstrates that this binding protein is a more sensitive marker for insulin resistance than other things we look at," said Dr. Stuart Weiss, an endocrinologist at New York University Medical Center.

Weiss was excited by the possibility of using RBP4 to track the progress of diet or exercise programs in people with diabetes or at risk for the disease.

"Whatever I can do to get people motivated to go for a stroll after dinner, get on the treadmill, or even just get off the bus a stop earlier is helpful, and the thought that an early disease marker might encourage people to do that is very exciting," he said. "Even just a 15-minute walk has been shown to increase outcomes in insulin sensitivity."

More information

To learn more about insulin resistance and pre-diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases.

SOURCES: Barbara Kahn, M.D., chief, division of diabetes, endocrinology and metabolism, Beth Israel Deaconess Medical Center, and professor, medicine, Harvard Medical School, Boston; Stuart Weiss, M.D., endocrinologist, New York University Medical Center, and clinical assistant professor, New York University School of Medicine, New York City; June 15, 2006, New England Journal of Medicine
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