Protein represents new target in the treatment of diabetes

According to a new study elevated levels of a molecule called RBP4 (retinol binding protein 4) forecast the early stages of the development of insulin resistance, a major cause of type 2 diabetes as well as cardiovascular disease and metabolic syndrome.

Researchers at Beth Israel Deaconess Medical Center (BIDMC), say their findings offer a potential new target for the development of anti-diabetic therapies to lower serum RBP4 levels, as well as an early means of identifying individuals who are at risk of developing diabetes.

The revelation could very well lead to better screening tests for insulin resistance, and help in assessing the effects of diet and exercise programs on reducing diabetes risk, as well as new therapies targeted at lowering the levels of the protein.

Barbara Kahn, MD, Chief of the Division of Diabetes, Endocrinology and Metabolism at BIDMC and Professor of Medicine at Harvard Medical School says type 2 diabetes is a rapidly increasing epidemic in the Western world and is increasingly occurring in childhood, and for the first time in more than a century now threatens to shorten life span in the U.S.

Insulin resistance develops when the body's muscles, fat and liver cells lose the ability to respond to the hormone insulin, and because insulin is necessary to enable the body to take up sugar from blood and convert it into energy, this impairment results in a buildup of glucose in the bloodstream.

Experts say that insulin resistance not only predisposes individuals to type 2 diabetes, it is also a major risk factor for cardiovascular disease.

Co-author Dr .Timothy Graham, an investigator in the Kahn laboratory says it is often difficult to distinguish individuals with and without insulin resistance; in a previous study conducted on animals, Kahn's laboratory made the discovery that RBP4, a protein secreted from fat, formerly recognized only for its role in the transport of vitamin A, can cause insulin resistance.

The researchers were eager to discover if the same applied in humans.

In order to determine whether levels of RBP4, as measured in blood, correlated with the presence or absence of insulin resistance, the researchers looked at blood samples from people from three different areas: California, Sweden and Germany.

They chose three distinct groups of people;

• lean people, obese people without diabetes and obese people with type 2 diabetes;
• people with normal glucose metabolism, impaired glucose metabolism or type 2 diabetes;
• and non-obese people with a strong family history of type 2 diabetes.

The first group 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 in effect means that RBP4 might possibly be used as a screening test for those at high risk, as a measure of who is more likely to develop diabetes.

Dr. Kahn says the study found an association between RBP4 and insulin resistance, but the research did not confirm whether or not RBP4 is simply a marker of insulin resistance or if it actually causes insulin resistance.

According to the American Diabetes Association as many as 21 million Americans suffer from diabetes, and between 90 percent to 95 percent of those people have type 2 diabetes; insulin resistance is often a precursor to the disease.

The researchers also 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.

The good news was that exercise at a moderate pace three to four times a week for about 60 minutes at a time lowered RBP4, a protocol, says Kahn, that many people could carry out.

Kahn says that collectively, the findings show that RBP4 is a useful marker for improvements in therapies and the fact that the protein may play a causal role in insulin resistance in humans may help clinicians to better manage the growing diabetes epidemic.

She says her team is interested in doing a study to see if lowering RBP4 levels would be helpful in people with diabetes, but as RBP4 is used for vitamin A metabolism, it could not be completely eliminated but could just be reduced to normal levels.

Experts say the possibility of an early disease marker for type 2 diabetes in the general population is exciting and the findings might encourage people to do more exercise.

More information about insulin resistance and pre-diabetes can be found from the National Institute of Diabetes and Digestive and Kidney Diseases.

This study was funded, in part, by grants from the National Institutes of Health, the American Diabetes Association, the Swedish Diabetes Association, and the Takeda Pharmaceutical Company, Ltd.

The research is published in the current issue of the New England Journal of Medicine.