A study in the June 15 issue of The New England Journal of Medicine (NEJM) reveals that elevated levels of a molecule called RBP4 (retinol binding protein 4) can foretell early stages in the development of insulin resistance, a major cause of type 2 diabetes as well as cardiovascular disease.

The new findings, led by researchers at Beth Israel Deaconess Medical Center (BIDMC), 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 -  before the onset of overt disease.

“Type 2 diabetes is a rapidly increasing epidemic in the Western world,” explains senior author Barbara Kahn, MD, Chief of the Division of Diabetes, Endocrinology and Metabolism at BIDMC and Professor of Medicine at Harvard Medical School. “Since it is now occurring even in childhood, predictions indicate that it could shorten lifespan in the U.S. for the first time in more than a century.”

Insulin resistance develops when the body’s muscles, fat and liver cells lose the ability to respond to the hormone insulin. 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.

“Insulin resistance not only predisposes individuals to type 2 diabetes, it is also a major risk factor for cardiovascular disease,” adds co-lead author Timothy Graham, MD, an investigator in the Kahn laboratory. “Unfortunately, in the clinical setting, it is often difficult to distinguish individuals with and without insulin resistance.”

Last year, in a study conducted in animals, Kahn’s laboratory made the discovery that RBP4, a protein secreted from fat, can cause insulin resistance. Prior to this, the molecule was recognized only for its role in the transport of vitamin A.

In this new research, Graham, together with co-lead author Qin Yang, MD, PhD, set out to determine whether levels of RBP4, as measured in blood, correlate with the presence or absence of insulin resistance. (Study subjects represented three separate cohorts from San Diego, California; Goteberg, Sweden; and Leipzig, Germany.)

They first studied individuals with either obesity, impaired glucose tolerance (a “pre-diabetic” state), or with type 2 diabetes, comparing the blood levels of RBP4 in these insulin-resistant subjects with levels found in non-obese healthy subjects. Their results showed that not only were RBP4 levels higher in all cases in which insulin resistance was high, but that elevated serum RBP4 was also closely associated with components of the metabolic syndrome, including increased body mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure, as well as decreased levels of high-density lipoprotein (HDL), or good, cholesterol.

The study was then extended to subjects with normal body weight and normal blood glucose, but with a strong family history of type 2 diabetes. “These are people who appear healthy, but have a high risk of developing diabetes due to their genetic background,” explains Ulf Smith, MD, PhD, of Sahlgrenska Hospital, Goteberg, Sweden, where this group of subjects was based. As predicted, the investigators found elevated RBP4 levels among this group as well.

Finally, the authors tested whether a therapeutic intervention -  in this case, exercise -  could lower RBP4 levels and increase insulin sensitivity. They found that all of the people who improved their insulin sensitivity with exercise also lowered their serum RBP4 levels. Among the one-third of the subjects who did not improve their insulin sensitivity, neither did RBP4 levels go down.

“Collectively, these findings tell us that RBP4 is a useful marker for therapeutic improvement and that this protein could play a causal role in insulin resistance in humans, just as our lab previously showed in mice,” says Kahn. Furthermore, she adds, because RBP4 levels consistently corresponded with insulin resistance - even among lean subjects whose genetic risk for the development of diabetes might otherwise be overlooked - this protein could be an important marker for type 2 diabetes among the general population.

“Being able to determine diabetes risk well before the onset of symptoms could provide an important opportunity for patients to take preventive measures,” she adds. “For those who are overweight or sedentary, this could mean making changes to their diet and fitness routines. For those who are lean and fit, but have a family history of type 2 diabetes, this could mean taking antidiabetic medication. Either way, these findings could help clinicians to better manage this growing epidemic.”

In addition to Kahn, Graham and Yang, study coauthors include Christopher Watson of BIDMC; Matthias Bluher, MD and Andreas Oberbach, MD, of the University of Leipzig Medical Center, Germany; Ann Hammarstedt, PhD, Per-Anders Jansson, MD, PhD, and Ulf Smith, MD, of Sahlgrenska University Hospital, Goteborg, Sweden; and Theodore Ciaraldi, PhD and Robert Henry, MD, of the Veterans Affairs San Diego Healthcare System.

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.

Beth Israel Deaconess Medical Center