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BOSTON, June 15 — High levels of retinol binding protein 4 (RBP4), which transports vitamin A as its main job, may be an early warning sign for insulin resistance and type 2 diabetes, according to researchers here.

Serum levels of retinol binding protein 4 (RBP4) are correlated with insulin resistance in a range of patients at risk for diabetes, found Barbara Kahn, M.D., of Beth Israel Deaconess Medical Center and Harvard Medical School, and colleagues.

What's more, therapeutic interventions that lowered insulin resistance also lowered serum RBP4 levels, Dr. Kahn and colleagues reported in the June 15 issue of the New England Journal of Medicine.

Dr. Kahn's lab showed last year that RBP4, in animals, can actually cause insulin resistance. In this study, they looked at three cohorts of patients, trying to tease out the link between RBP4 and insulin resistance in humans.

The first cohort consisted of people with obesity, impaired glucose tolerance, or frank diabetes. The researchers compared their serum RBP4 with levels found in the second cohort, a group of non-obese healthy participants.

Mean serum levels were elevated in both the diabetic and non-diabetic obese participants, compared with the healthy controls, and were:

• Significantly correlated with body mass index (at P=0.001).
• Significantly correlated with fasting insulin (at P Inversely correlated with the rate of glucose disposal (at P=0.009).

Elevated serum RBP4 was also closely linked to elements of the metabolic syndrome, including increased waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure, as well as lower levels of HDL cholesterol.

In the third cohort—those with a normal body weight and blood glucose but a strong family history of type 2 diabetes—the researcher also found elevated serum RBP4, compared with healthy controls without a family history of diabetes.

The researchers also looked at the effect of exercise and found that a month of exercise training had variable effects—some participants increased insulin sensitivity and some did not. But in all cases, the serum RBP4 tracked insulin sensitivity, they reported. If insulin sensitivity increased, RBP4 levels fell; if insulin sensitivity did not change, neither did RBP4.

"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," Dr. Kahn said.

The protein could also be a useful test among lean patients whose genetic risk for the development of diabetes might otherwise be overlooked, she said.

"Being able to determine diabetes risk well before the onset of symptoms could provide an important opportunity for patients to take preventive measures," Dr. Kahn said.

In an accompanying editorial, Kenneth Polonsky, M.D., of Washington University in St. Louis, called the findings "interesting and important," said but fall short of defining what role RBP4 plays in the pathogenesis of diabetes.

It could be that the protein is just a biomarker that's correlated with insulin resistance or it could have a causal role, Dr. Polonsky said, but the cross-sectional design of Dr. Kahn and colleagues' study does not permit conclusions to be drawn either way.

However, he said, the study raises questions that should prompt future investigation, including:

• What signaling pathways inhibited or stimulated by RBP4 could affect insulin activity?
• Is genetic variation in the gene for RBP4 linked to variation in the risk of insulin resistance or diabetes?
• Can administration of a synthetic retinoid, which reduces serum RBP4 levels, improve insulin sensitivity?