Hormone Found as Link Between Obesity, Diabetes
Researchers have discovered what appears to be a key link between diabetes and its single greatest risk factor: obesity.
The finding, reported in today’s issue of the journal Nature, offers the prospect of more powerful drugs--with fewer side effects--for treating the disease, which affects 15 million Americans and more than 100 million people worldwide.
Scientists have known that obesity is strongly linked to diabetes, but did not understand how the extra pounds interfere with sugar metabolism. Now, University of Pennsylvania researchers have discovered a hormone, called resistin, that is released by fat cells and that interferes with the activity of insulin, producing type 2 diabetes.
Resistin appears to be “at least part of the missing link between obesity and diabetes,” according to Dr. Jeffrey S. Flier of the Beth Israel Deaconess Medical Center in Boston, who wrote an editorial about the paper in the same issue of Nature.
“This is an extraordinarily important paper with potentially major clinical implications for people with obesity and type 2 diabetes,” said Dr. Allen Spiegel, director of the National Institute of Diabetes and Digestive and Kidney Diseases. In one study, he added, the team has discovered a novel hormone secreted by fat cells, explained how the newest family of anti-diabetes drugs works and provided a key link between obesity and diabetes.
But experts cautioned that the hormone has so far been studied only in mice. “It will need to be confirmed in humans,” said Dr. Luigi Meneghini of the Diabetes Research Institute in Miami. “But it’s exciting work.”
About 10% of diabetes patients in the United States have type 1, in which the pancreas is no longer able to produce insulin, a hormone that helps cells throughout the body use sugars in the bloodstream. They are treated with insulin injections.
The rest have type 2 diabetes, in which the pancreas produces insulin but cells do not respond to it properly. The pancreas produces more and more insulin, but can eventually become exhausted and no longer able to produce the hormone. Those patients may also have to take insulin shots.
The disease is one of the most costly health problems in America because of its devastating complications, which include blindness, kidney failure and nerve damage (which can lead to limb amputation), as well as an increased risk of heart attack and stroke. Overall, diabetes causes nearly 190,000 deaths in the United States each year and accounts for $98 billion in medical costs and lost productivity.
Public health authorities have become alarmed because the incidence of type 2 diabetes, triggered by a rising incidence of obesity, is growing at an unprecedented rate. A recent study by the Centers for Disease Control and Prevention found that the overall incidence grew by 33% between 1990 and 1998.
Perhaps more disturbing, a disease that was once an affliction primarily of the elderly is surging among younger people--even children. During the 1990s, that same survey found that the incidence among people in their 30s grew by 70%.
The new findings, however, suggest that it may be possible to break the link between obesity and diabetes and slow that growth. The hope is to develop drugs that would specifically block or deactivate resistin.
Dr. Mitchell A. Lazar and his colleagues at the University of Pennsylvania School of Medicine discovered the new hormone while studying a new family of anti-diabetes drugs called thiazolidinediones, or TZDs. These drugs include pioglitazone (known by the trade name Actos), rosiglitazone (Avandia) and the recently banned troglitazone (Rezulin). All reduce insulin resistance, but they have a number of side effects.
To determine how TZDs work, the researchers exposed mouse fat cells to the drugs to see which genes in the cells were turned on or off.
“It was kind of like panning for gold,” Lazar said. When they sorted through the genes, they were “left with these few nuggets.” One of the nuggets proved to be the hormone they named resistin.
They found that resistin circulates in the blood of normal, healthy mice, falling after a fast and rising after a feeding. It is dramatically higher in obese mice.
Moreover, when Lazar’s team synthesized resistin and infused it into healthy mice, the animals’ blood sugar levels increased and they eventually developed the symptoms of diabetes.
When the researchers made antibodies against resistin and injected them into mice with diet-induced obesity to block the hormone’s effects, the treatment improved their insulin action and lowered blood glucose levels.
Lazar and his colleagues have examined the human genome data and found that the gene for resistin is present there as well, although the human hormone has not yet been isolated and no studies have been performed in people.
But if the observations in mice are replicated in humans, Lazar said, “measuring resistin levels could help diagnose people at risk for type 2 diabetes. If resistin is really causing insulin resistance, then lowering levels of the hormone or blocking its action could constitute a new treatment.”
Initially, researchers may be able to develop new TZD analogs or similar drugs that target the production of resistin in fat cells more specifically. Current TZDs provoke a number of other reactions as well, which is why they have side effects.
Scientists are also racing to identify the receptor through which resistin binds to other cells in the body to increase insulin resistance. “Then that receptor becomes an extraordinarily attractive target for the development of [drug] antagonists that block resistin action,” Spiegel said.
“In principle, we could uncouple obesity and the development of diabetes,” he added.
Lazar is also working to uncover the normal role of resistin. He speculates that it may have developed as a response to periods of low food supply during the human past.
Whether the discovery produces new drugs or not, Meneghini added, the paper is important because “it focuses attention on the fat cell as one of the key components of insulin resistance.” Studying the cells, he said, should provide a number of new insights into the cause of diabetes.
