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WebMD Medical News

Reviewed by Louise Chang, MD

Nov. 6, 2007 -- Obesity leads to insulin resistance and diabetes, but

not if a key inflammatory pathway is blocked, mouse studies show.

Abdominal obesity is a key risk factor for type 2 diabetes. As people

gain more and more belly fat, they become more and more resistant to

insulin. Their bodies have to make more and more insulin to control

their blood sugar. Eventually, they develop diabetes.

Why does this happen? Scientists have found that one of the body's

chemical signals, called JNK1, is needed both for the accumulation of

abdominal fat and for obesity-related insulin resistance. Mice

lacking the JNK1 gene can eat a high-fat diet without getting fat and

without getting diabetes.

But can you become obese without getting diabetes? The surprising

answer seems to be yes.

That is, if the JNK1 signal is blocked in the bone-marrow-derived

immune cells called macrophages but not in other tissues. The finding

comes from mouse studies by University of California, San Diego

researchers Jerrold Olefsky, MD, and colleagues.

Macrophages, the researchers find, need JNK1 to keep up a low-level,

obesity-triggered inflammatory response throughout the body. It is

this immune response -- not obesity itself -- that leads to insulin

resistance and diabetes.

" If we can block or disarm this macrophage inflammatory pathway in

humans, we could interrupt the cascade that leads to insulin

resistance and diabetes, " Olefsky says in a news release.

It's much easier to find a drug that affects bone-marrow-derived

cells than it is to find one that affects other cells. The findings

thus take researchers one step closer to a new class of

diabetes-preventing drugs.

" We aren't suggesting that obesity is healthy, but indications are

promising that, by blocking the macrophage pathway, scientists may

find a way to prevent the type 2 diabetes now linked to obesity, "

Olefsky says.

The findings appear in the November issue of Cell Metabolism.

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