Study finds Type 2 diabetes partly reversible

April 19, 2011, 2:04 a.m.

Researchers at the School of Medicine have discovered that type 2 diabetes is at least in part an autoimmune disease. Their report, published in this month’s Nature Medicine, shows that B-cells appear in the inflammation of the visceral fat that precedes diabetes, and controlling them with drugs can actually prevent insulin resistance in mice on high-fat diets.

Study finds Type 2 diabetes partly reversible
(SERENITY NGUYEN/The Stanford Daily)

“It’s exciting to see this kind of discovery, because I think its going to turn out to be important going forward in how we ultimately manage this really common and serious disease,” said pathology professor Edgar Engleman, whose lab conducted the study.

Type 2 diabetes occurs after the body’s tissues become resistant to insulin, the hormone that triggers cells to take up sugar from the blood stream. This leads to unregulated fluctuations of blood sugar that require constant management. Type 2 diabetes has always been viewed as a metabolic disease, though the underlying cause of insulin resistance has never been determined.

“The main thing is that no one has really known why your tissues become resistant to insulin,” said Dan Winer, one of the first authors of the study. “The theory we’re putting forward is that the inflammation that occurs in different parts of your body, one of them being the deep visceral fat, contributes to insulin resistance. And part of that is insulin resistance that is occurring because of your immune system attacking your own body’s proteins.”

The study identified key B-cells in the inflammatory response for the first time, building upon past work done by the lab about the inflammation that precedes diabetes. B-cells normally tell the body to react to specific invading diseases by releasing antibodies and chemical signals called cytokines.

The study showed that in type 2 diabetes, the B-cells instruct the body to react to its own proteins, which appears to cause cells to resist insulin. Mice treated with a B-cell depleting drug called anti-CD20 did not develop insulin resistance in response to a high fat diet, while mice not on the drug did develop insulin resistance.

In addition, the researchers examined antibodies in the blood of 32 obese men, half with insulin resistance and half without. Patients with insulin resistance all had a distinct profile of antibodies consistent with those found in insulin resistant mice. The antibodies were not present in patients that were still sensitive to insulin. These preliminary findings suggest that the B-cell immune response in diabetic mice also occurs in diabetic humans.

“We’ve identified a set of antibodies that are pathogenic — that cause insulin resistance — which is a new finding,” Winer said.

He acknowledged that this finding “doesn’t exclude the possibility” that some of the antibodies found in insulin-sensitive, obese patients might be protective.

The new role of antibodies has also made Winer hopeful that someday doctors could prevent insulin resistance with drugs that regulate the immune system or even with a vaccine.

“What’s fascinating to me as a physician is that I have always thought of this as a chronic and essentially irreversible disease, and once you get started, the only thing you can really do is control it,” Engleman said. “That’s what I had learned. And what we find is that’s not really true; in fact, this appears to be a disease that’s at least partially reversible.”

However, Winer and Engleman both caution that immune therapies are still a ways off. Most of the work done so far has been in animal models, and a link needs to be firmly established in humans in more extensive studies. Controlling the disease with immunosuppressants is also risky, since the immune system is necessary for fighting off infection.

“The idea of using immune drugs is something that I view as an experiment that has to be done as opposed to something we know is going to work,” Engleman said.

About one in four Americans has diabetes, making the disorder one of the most prevalent in the United States. This growing problem is why Winer and Engleman both hope to continue working on the disease.

“It’s too big a problem to not want to continue to work on it,” Engleman said. “It’s too important.”

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