Scientists at Joslin Diabetes Center have discovered why excess weight leads to low-grade inflammation, which hampers the body's ability to use insulin. They found that the "master switch" of this inflammation is activated in the liver by weight gain. And they showed it can be turned off by salicylates, a class of drugs that includes aspirin.

This, is a major milestone in understanding why being overweight can lead to a host of health problems, including type 2 diabetes and heart disease. An estimated 18 million Americans have type 2 diabetes, including an increasing number of young people. They are two to four times more likely to have cardiovascular disease.

"We zeroed in on a factor called NF-kB," said principal investigator Steven E. Shoelson, M.D., Ph.D., Helen and Morton Adler Chair and head of the Section on Cellular and Molecular Physiology at Joslin, and Professor of Medicine at Harvard Medicine School.

"When we activated this factor in the liver of laboratory animals, it stimulated a cascade of inflammatory responses," said Dr. Shoelson. "The result was dramatic -- including insulin resistance consistent with type 2 diabetes.

"We previously knew that in obesity, the liver becomes fatty and that it accumulates fat faster than other organs and tissues," Dr. Shoelson continued. "But until now, we didn't know fat in the liver could orchestrate the entire inflammatory process that results in insulin resistance, both locally and throughout the body."

The researchers were inspired by previous clinical studies of human patients at Joslin, driving them to seek answers in the laboratory. Those studies had shown that overweight people who have insulin resistance had slightly higher activity levels of NF-kB and other substances normally found in inflammation. Intrigued that fatty tissue may activate a small but measurable level of inflammation, they set out to discover the cellular pathway.

They focused on healthy lean mice -- with no weight problems predisposing them to type 2 diabetes. Using genetic techniques, the research team turned on the gene that expresses NF-kB. They then measured the insulin levels in the bloodstream; if higher than normal, it's a telltale sign of insulin resistance because the body is not using the available insulin. They also measured blood glucose levels to see if they were higher, consistent with diabetes. And they looked for substances produced along the inflammation pathway.

"Unlike in an acute infection, when NF-kB levels shoot up about 50-fold, the inflammation seen in these mice just simmered -- only about 3-fold," said Dr. Shoelson. "But their insulin levels and blood glucose levels were high, what we'd expect in type 2 diabetes. In effect, we had induced diabetes by turning on low-grade inflammation." Among the markers in the cascade was C-reactive protein, now the focus of considerable interest in cardiovascular research.

The Joslin researchers also found that the NF-kB "master switch" could be inhibited by the salicylate family of drugs. "These drugs -- among the safest drugs known -- can do a surprisingly good job of toning down this inflammation," said Dr. Shoelson.
"But more studies need to be done before we can make recommendations to patients," he cautions. "For now, the best advice for preventing the onset of type 2 diabetes is to shed those extra pounds, eat a healthy diet and exercise regularly."

Source: Diabetes in Control.com: Nature Medicine, Feb.2005.