Insulin-resistance gene defect identified.

Insulin, the hormone that directs metabolism of glucose in the body, has long been suspected to have a link to fat breakdown. Even though insulin doesn't itself guide fat metabolism, scientists have noticed that people with a lot of fatty acids--derivatives of fats--in the bloodstream don't use insulin efficiently, a condition called insulin resistance.

Insulin resistance, which frequently appears in obese people and those with high blood pressure, is a hallmark of type II diabetes. In contrast, type I, or juvenile, diabetes arises because pancreas cells fail to produce enough insulin.

A team of European and U.S. scientists now reports that insulin-resistant rats have a defect in a gene involved in fat metabolism. The gene, Cd36, encodes a protein that sits on the surface of fat cells, muscle cells, and heart cells.

Among its many roles, the CD36 protein transports fatty acids into a cell for processing. A dearth of CD36 leaves these fatty acids in the bloodstream, which not only abets obesity but seems to disrupt the insulin pathway and prevent cells from taking in glucose properly, says study coauthor Timothy J. Aitman, a diabetologist at the MRC Clinical Sciences Centre in London.

The researchers compared rats bred to have high blood pressure with a group of normal rats. They found Cd36 defects only in hypertensive rats that were also insulin resistant. Moreover, a group of mice with an overactive Cd36 gene proved to have low concentrations of fat in the blood. The scientists report their findings in the January NATURE MEDICINE.

"This is a very intriguing study," says Ping H. Wang, an endocrinologist at the University of California, Irvine. "This is the first report actually showing, at the genetic level, a defect that may link insulin resistance to fatty acid metabolism."

"If human diabetes is shown to be due, even in some cases, to CD36 deficiency, then it gives us a handle on a primary cause of the disease," says Aitman.

Insulin controls glucose metabolism by ushering the sugar into cells. The exact pathway is still unclear, as is the means by which excess fatty acids disrupt that process. However, the new findings suggest a genetic basis for a theory holding that, in the body, fat metabolism has priority over sugar use.

"With free fatty acids around, you don't burn a lot of glucose," says molecular biologist Graeme I. Bell of the Howard Hughes Medical Institute at the University of Chicago. "You burn the fat first."

"Diabetes has been viewed as a disorder of sugar metabolism," Aitman says. "But if [defective] Cd36 is a cause of insulin resistance ... some forms of diabetes may be more a result of defective fat metabolism."

Noting that obese people often develop high blood pressure and type II diabetes, Wang says that the new study "provides a very good argument" that the same genetic defects could underlie these three disorders.

The Cd36 genetic defect appears in roughly 2 to 3 percent of Japanese, Thai, and African people but in less than 1 percent of whites in the United States. Type II diabetes, however, currently affects about 10 percent of African Americans and 7 percent of U.S. whites.