The number of Americans with diabetes doubled between 1980 and 2003 and more than 13 million are currently diagnosed with the disease. Being overweight or obese has long been recognized as a risk factor for type 2 diabetes. Now the results of a new study are clarifying the nature of the link between weight and diabetes. According to a report published today in the journal Nature, a protein released by fat tissue causes insulin resistance in mice.

The main function of the protein RBP4 is to deliver vitamin A to body tissues. In previous studies, researchers had observed elevated levels of RBP4 in diabetes patients, but they did not believe it to be a causal factor. Barbara B. Kahn of the Beth Israel Deaconess Medical Center and Harvard Medical School and her colleagues studied mice engineered to lack a glucose transporter gene usually expressed in fat tissue, which made them more likely to develop insulin resistance and diabetes than control animals are. They found that these animals have 2.5 times the normal level of RBP4. When the modified mice received an insulin-sensitizing drug, however, their RBP4 levels returned to normal. The scientists also raised RBP4 levels in mice--through genetic manipulation in some subjects and drugs in others--and found that in both cases the higher protein levels can cause insulin resistance. "Being resistant to insulin is one of the major causes of diabetes," Kahn says. "And even in the absence of diabetes, insulin resistance is a major risk factor for heart disease and early mortality."

The team additionally demonstrated that lowering RBP4 levels in insulin-resistant mice using a drug that causes excretion of the protein improves their condition. Because overweight people with diabetes have roughly twice as much RBP4 in their blood as lean people do, the same approach might some day work for humans. Says Kahn: "RBP4 could prove to be a novel target for developing anti-diabetic therapies."