Scientists discover “master switch” that triggers insulin resistance and type 2 diabetes

“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.

Shoelson said that activating NF-kB in the livers of laboratory animals incited inflammatory responses.

Up until that point, Shoelson continued, his team “didn’t know fat in the liver could orchestrate the entire inflammatory process that results in insulin resistance, both locally and throughout the body.”

Previous studies had shown that overweight people with insulin resistance had slightly higher activity levels of NF-kB and other substances normally found in inflammation. Intrigued that fatty tissue may activate a level of inflammation, researchers set out to discover the cellular pathway.

Focusing on healthy, lean mice and using genetic techniques, the researchers turned on the gene that expresses NF-kB, then measured the insulin levels in the bloodstream. Abnormally high levels are a telltale sign of insulin resistance. 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 Shoelson. “But their insulin levels and blood glucose levels were high, what we’d expect in type 2 diabetes.”

The Joslin researchers also found that the NF-kB “master switch” could be inhibited by the salicylate family of drugs.