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Resisting insulin
A new hormone may be the link between obesity and type II diabetes
By Bijal P. Trivedi

Roughly 16 million Americans have diabetes, and the majority of them also suffer from obesity. Yet the link between the two diseases, at least in humans, remains unclear. Now scientists have discovered a protein that may tie the two together and provide a new target for anti-diabetic drugs.

Scientists have found that mice that are either obese or diabetic have high levels of a single protein called resistin.

"Resistin seems to have a direct effect on fat cells and that's what is so exciting," says Mitchell Lazar, an endocrinologist at the University of Pennsylvania School of Medicine, whose team discovered resistin. If high levels of resistin lead to diabetes, then the therapy would be to block it, he added.

When normal mice were fed a high-fat diet, the animals became obese and they developed a diabetic resistance to insulin within four weeks. The researchers found that as the glucose increased, so did the resistin levels. When the scientists blocked the protein, the levels dropped back down.

Lazar found that giving resistin to healthy mice reduced their glucose uptake. Conversely, treating the mice with anti-resistin antibodies, which bind to resistin and hinder the protein, rendered the cells more sensitive to insulin and decreased blood glucose.

Experiments using fat cells alone produced similar results; anti-resistin antibodies increased glucose uptake by 42 percent, whereas treating cells with resistin reduced uptake.

More than 90 percent of all diabetics suffer from the type II form of the disease that is characterized by "insulin resistance." People with type II continue to produce insulin, but the insulin is unable to trigger uptake of blood glucose into muscle, liver and fat cells. If high blood sugar remains untreated, heart disease, blindness, kidney failure and nerve damage result. The goal of anti-diabetes drugs is to keep blood glucose levels low.

Lazar's team discovered resistin using a new class of TZD [thiazoladinediones] anti-diabetic drugs that were developed in the late 1990s. Lazar took fat cells, exposed them to TZDs and then scanned for genes that were turned off or whose activity was significantly reduced by the drugs. The gene that stood out was resistin.

"This was the first clue that resistin would play a major role," says Lazar. Further experiments showed that the gene is also found in humans and turns on only in fat tissue.

It is unlikely that resistin is the only connection between obesity and diabetes. The question is, how big a part does it play? To find the answer, Lazar's team is creating a mouse that lacks the resistin gene.

"This will help us to determine whether eliminating resistin protects mice from diabetes," says Lazar. If Lazar's hypothesis is correct, these mice should be able to eat fatty foods and become obese without becoming diabetic. The team also intends to create a second mouse that produces too much resistin—the opposite of a resistin-gene knockout. This would reveal whether producing a high resistin level in a thin animal is sufficient to cause diabetes.

The Philadelphia team will expand their studies to examine human serum from diabetes patients, and from obese people at risk for developing the disease, to determine whether resistin levels are above normal. If results in humans mimic those seen in mice, the work could lead to new treatments for diabetes and a stronger understanding of glucose metabolism.

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Steppan, C. M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307-312 (January 18, 2001).
Steppan, C. M. et al. A family of tissue specific resistin-like molecules. Proc Natl Acad Sci U S A 98, 502-506 (January 16, 2001).

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