Diabetes: clarifying the role of obesity.

Roughly 90 percent of diabetics suffer from a form of the disease described as Type II, or non-insulin-dependent. Though obesity constitutes one of the most common predisposing factors for this type of diabetes, clinicians have never known why. Now a trio of Boston-based researchers has uncovered surprising clues - opening up the prospect of managing this often lethal disease more effectively with drugs.

In the Jan. 1 SCIENCE, Bruce M. Spiegelman and his colleagues at the Dana-Farber Cancer Institute report on animal studies showing that obesity somehow stimulates fat cells to overproduce a hormone-like substance known as tumor necrosis factor-alpha (TNF-alpha).

Compared to lean rodents, obese animals of the same strain showed a sharp elevation in the activity of genes responsible for producing TNF-alpha. Not only did obese animals have more fatty tissue to make the compound, but each of their fat cells secreted about twice as much of the hormone-like substance as did those of lean cohorts. This trend help up in at least four animal models of obesity: All four generally express insulin resistance and other symptoms of developing or mature diabetes.

High levels of TNF-alpha have been shown capable of causing both septic shock and a wasting syndrome common in cancer victims. But Spiegelman's team now reports finding that a much smaller excess of TNF-alpha depresses the expression of the genes responsible for producing the proteins adipsin and glut4.

Though adipsin's function remains unknown, Spiegelman notes that glut4 enables glucose to pass through cell membranes under the regulation of insulin. Indeed, work by him and others has shown that the activity of the genes coding for these proteins is typically low in animals suffering from obesity-linked insulin-resistant syndromes.

The Dana-Farber scientists also showed that when TNF-alpha's effects are blocked with a drug that binds to and disarms the molecule, obese animals immediately experience a remarkable increase in their responsiveness to insulin. A primary feature of obesity-linked diabetes is the patient's resistance to insulin, the chief hormone responsible for lowering concentrations of sugar in the blood.

Spiegelman says that, taken together, these new data suggest that if obese diabetics similarly overproduce TNF-alpha, clinicans may eventually be able to control a patient's blood sugar concentrations with drugs that block TNF-alpha. Several such drugs are currently under development for treating septic shock.