Steven Shoelson

Back in 1876, a German physician reported that big doses of salicylates–a chemical cousin of aspirin–provided relief from high "urine sugars" in an obese man who presumably had type 2 diabetes. At the turn of the century and again in the late 1950s, a few similar clinical case studies showed equally dramatic results.

Rediscovering these results while searching the scientific literature, investigator Steven Shoelson and colleagues have found a molecular mechanism that–when triggered–can cause insulin resistance, a precursor to type 2 diabetes. More importantly, the mechanism can be turned off, even in overfed animals and people, suggesting an immediate molecular target for drug development to battle diabetes.

Shoelson, the Helen and Morton Adler Chair at Joslin Diabetes Center and professor of medicine at Harvard Medical School, inaugurated a distinguished lecture series by the Department of Genetics and Complex Diseases at HSPH.

Type 2 diabetes affects an estimated 18 million Americans, according to the National Institutes of Health (NIH), and many more people worldwide. Those numbers are expected to balloon with the obesity epidemic. Obesity causes tissues in the body to become insulin resistant, or unresponsive to insulin’s action. In an effort to overcome this unresponsiveness, pancreatic beta cells are forced to make more insulin, which nudges energy-providing glucose into cells. Eventually, beta cells become too fatigued to pump out enough insulin to overcome the growing resistance of the cells to the hormone. In some people, a combination of insulin resistance, sedentary lifestyle, poor diet, and genetic susceptibility can progress to type 2 diabetes. Exercise and weight loss can help stave off the disease.

High doses of salicylates, including stomach-churning doses of aspirin, can reverse the major symptoms of type 2 diabetes by muzzling a molecule, IKK-beta, reported Shoelson and colleagues in Science three years ago. Blocking the molecule stops an inflammatory reaction–and as a result, allows the body to take up more insulin.

The finding has implications for both obese and non-obese people. In animal studies, Shoelson and his colleagues have found that a diet high in fat activates a transcription factor, NF-kB, that controls inflammation. The transcription factor is in turn controlled by IKK-beta, the target for salicylates.

The scientists tested whether activation of NF-kB would cause insulin resistance by using genetically altered transgenic mice. As it turned out, activating the transcription factor in the fat or livers of the mice caused insulin resistance–even in thin, normal mice. Conversely, inhibiting the transcription factor prevented insulin resistance–even in obese mice. Blocking this molecular pathway would theoretically decrease the risk of type 2 diabetes in people, if scientists learn that the mice findings can apply to humans.

Shoelson’s studies support emerging evidence that a low-grade inflammation underlies the pathogenesis of type 2 diabetes.

So why not just take aspirin to reverse the effects of type 2 diabetes? The doses needed would be so high that many people would find the side effects, which can include ringing in the ears and bleeding stomachs, to be intolerable. People would need to take five to eight grams of aspirin a day–doses used to control rheumatic fever and rheumatoid arthritis–to inhibit IKK-beta and the downstream chemical reaction.

Shoelson and his colleagues have tested 15 obese people with high doses of salsalate, a form of salicylate that is less irritating to the stomach lining. The effect appears to be just as potent. Preliminary results show lower circulating levels of glucose, triglycerides, free fatty acids, heptatic glucose production, inflammatory proteins, and accompanying clinical symptoms, Shoelson said. He and his colleagues are working with the NIH to expand the trial to about 200 people at three study sites in Boston, New Haven, and Los Angeles.

--CCM