Seeking the source of a sugar-storage flaw.

Seeking the source of a sugar-storage flaw

Most Type II diabetics have a disorder called insulin resistance, in which cells fail to respond fully to insulin's message to store sugar. Two small studies now strengthen the suggestion that these diabetics -- as well as seemingly healthy people with insulin resistance -- have a defect in the glucose transporter system that brings sugar into cells for processing, rather than a flaw in the insulin itself or in the cellular receptors for it. Though preliminary, the findings raise hopes that scientists might eventually develop treatments for insulin resistance, which some view as a very early sign of Type II diabetes.

Past attempts to unlock the mechanism behind insulin resistance focused primarily on the insulin receptor, a cell-surface protein that serves as this hormone's docking site. But in recent years, several studies have suggested that something goes wrong after insulin binds with its receptor, possibly involving a sugar-processing enzyme or the glucose transporters -- proteins in the cell that move to the cell surface to snare sugar from the bloodstream and deliver it into the cell for processing. At this week's meeting of the American Diabetes Association, held in Atlanta, researchers reported new results that add to the evidence implicating glucose transporters.

Scientists at the Yale University School of Medicine used nuclear magnetic resonance, a noninvasive technique, to study how well muscle cells take up glucose and convert it to an intermediate sugar form called glucose-6-phosphate. Douglas L. Rothman, Gerald I. Shulman and their colleagues measured baseline cellular levels of glucose-6-phosphate in four men with Type II diabetes and in four healthy men without insulin resistance. Next, they injected the eight volunteers with glucose and insulin -- a technique that approximates the postmeal "sugar surge" in the bloodstream. In the healthy men, muscle cells showed a 30 percent rise in intracellular glucose-6-phosphate levels 20 minutes after the injections, whereas the diabetics showed no increase. This may signal a malfunction in transporter proteins, the researchers speculate.

In a related report, W. Timothy Garvey and his colleagues at the Indiana University School of Medicine in Indianapolis suggest that people with insulin resistance have fewer transporter proteins to carry glucose into the cells. The team studied fat cells surgically removed from 11 lean control subjects, 11 obese people with Type II diabetes, and 11 obese people with insulin resistance but normal blood sugar levels. (Such people secrete more insulin to compensate for the cellular resistance to its message.)

Garvey's group found that the people with insulin resistance -- whether diabetic or not -- had fewer transporter proteins in their fat cells than did controls. In addition, he says, the results show decreased expression of the gene that directs fat cells to produce transporter proteins.

Scientists emphasize that the new findings remain preliminary and do not rule out other possible causes. "It's an evolving story," says Philip E. Cryer of the Washington University School of Medicine in St. Louis. Still, Garvey says, if researchers can pinpoint the defect responsible for insulin resistance, they may find a way to prevent progression to Type II diabetes, which usually strikes after age 40.