Sci. Aging Knowl. Environ., 19 February 2003
Resistance Is Futile
Insulin resistance doesn't presage diabetes unless the illness runs in the family
Key Words: hyperinsulinemia insulin-independent glucose effectiveness Bergman's Minimal Model
Abstract: Insulin resistance doesn't presage diabetes unless the illness runs in the family (Diabetes)
In older people, cells often stop listening to insulin, a hormone that helps control blood sugar concentration. Scientists have long believed that the condition is a precursor of diabetes, but a new study suggests that this form of cellular deafness foretells the illness only in people with close relatives who are diabetic. The study also hints at the existence of undiscovered genes that bollix sugar metabolism and foster disease.
More than 20% of Americans over age 60 develop diabetes. Patients make insufficient amounts of insulin, which normally prods cells to soak up glucose from the bloodstream, and their cells also respond weakly to the hormone--a condition known as insulin resistance. Several papers suggest that insulin resistance is an early indicator of incipient diabetes. In a study published in 1992, for instance, endocrinologist C. Ronald Kahn of the Joslin Diabetes Center in Boston and colleagues found that insulin sensitivity in diabetic patients was 60% lower than in healthy subjects. In addition, differences in insulin resistance were apparent more than 10 years before diabetes developed.
However, each of the patients in that study had two diabetic parents. To assess whether the results hold for a broader sample of the population, Kahn and colleagues expanded the study to include people who had no close relatives with the disease. As in their previous work, the researchers analyzed the results of glucose-tolerance tests, in which they inject sugar into patients and then draw blood samples at regular intervals to determine glucose and insulin quantities. From those measurements, the investigators calculated the patients' sensitivity to the hormone and the capacity of their cells to sop up glucose. Patients with below-average insulin sensitivity were 10 to 20 times more likely to develop diabetes if their parents had the disease than if their parents were not diabetic. For patients with nondiabetic parents, insulin resistance did not increase the odds of developing the illness. The disparity suggests that insulin resistance doesn't herald the onset of diabetes unless a parent also has the disease, says Kahn. Previous work has shown that insulin resistance is inherited; the new results imply that a separate set of genes dictates susceptibility to diabetes independent of insulin resistance. Although they don't know the function of these mystery genes, the researchers suspect that they disrupt insulin-related signaling within the cell.
"It's a nice paper because it gets at a fundamental question," says Gerald Shulman, an endocrinologist at Yale University. Lately, researchers in the field have been downplaying the importance of genes in diabetes's insidious progress and emphasizing factors such as diet and lack of exercise, says endocrinologist Mitchell Lazar of the University of Pennsylvania in Philadelphia. "This paper says, 'Yeah, we have to worry about genes.'" Pinpointing the genes that control disease susceptibility and deciphering their functions might help drug developers craft compounds that target the metabolic glitch. Such knowledge could also help doctors identify high-risk patients who need drug treatment or drastic diet and exercise programs. Ferreting out these genes won't be easy, Kahn cautions, but their discovery could reveal ways to make older cells listen up.
February 19, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150