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How Obesity Becomes Diabetes

Obesity and diabetes appear to go hand-in-hand, but the molecular details of the relationship have been unclear. Now, researchers have shown that a key enzyme rises up in obese mice and prevents cells from using insulin properly. The results provide a link between fat and glucose metabolism, as well as a potential target in the fight against the disease.

More than half of the adults in the United States are obese and face the risk of diabetes, which results when the body loses its ability to respond to insulin, the molecule that escorts glucose from blood into cells. Insulin resistance is thought to be triggered by free fatty acids and other molecules given off by certain kinds of fat. These molecules boost the activity of several enzymes, including one called JNK1. In test tube experiments, JNK1 turns off yet another molecule, called IRS-1, that normally assures that cells can take up insulin. So in principle, too much JNK1 could render cells unable to use glucose. To determine if JNK1 is the enzyme ultimately responsible for insulin resistance caused by weight gain, geneticist Gokhan Hotamisligil at the Harvard School of Public Health and colleagues deleted the gene for JNK1 in mice.

These mice ate an extravagantly rich diet, yet they didn't become resistant to insulin. Indeed, IRS-1 was active in the mice and helped maintain normal insulin function. In control mice given the same rich diet, IRS-1 was turned off, and the mice became insulin resistant. Because these two groups had the same amount of free fatty acids, the researchers conclude that JNK1 normally causes insulin resistance in response to fat. The team reports its results in the 21 November issue of Nature.

Calling the work "very interesting, very important," diabetes researcher Alan Saltiel at the University of Michigan Medical Center in Ann Arbor says that JNK1 "could be a good [therapeutic] target." He cautions, though, that a pill that prevents diabetes in obese people is many years away. In the meantime, Americans should keep at their exercise wheels.

Related sites
Gokhan Hotamisligil's lab at Harvard
Collaborator Michael Karin at the University of California, San Diego
American Diabetes Association