A hormone that can wreak havoc with the body by setting off harmful effects of stress may have a far more positive use: in a new way to treat diabetes.
The hormone, known as corticotropin-releasing factor, or CRF, has been implicated in anxiety, obesity, addiction and even Alzheimer's disease. The brain and other organs make CRF. It triggers a cascade of chemicals that ultimately produce cortisol and adrenaline and activate the body's "fight or flight" response. Under chronic stress, cortisol breaks down muscle, suppresses the immune system and raises the risk of high blood pressure.
But recently, researchers have showed that CRF increases both insulin secretion and production of the cells that make insulin in the pancreas, known as beta cells. Diabetes, which affects nearly 24 million Americans, involves the body's inability to properly use insulin to convert sugar into usable energy. The findings, which support a hunch that others in the field have had, point to a possible pathway for treatment of diabetes.
"The machinery that allows the cell to respond to the hormone has been found," says Wylie Vale, a professor of molecular neurobiology at the La Jolla, Calif., Salk Institute for Biological Studies, who discovered the structure of CRF in 1981. "We are exploring how this machinery is controlled under conditions such as diabetes and obesity. What we really want to do is understand the system." The research of Dr. Vale and his colleagues was reported in a December paper published in the Proceedings of the National Academy of Sciences.
With Type 1 diabetes, formerly known as juvenile diabetes, the body doesn't produce enough insulin. This happens because the immune system attacks and kills beta cells. These patients are treated with insulin injections.
The most common form of diabetes, associated with obesity, is Type 2. Here, the body doesn't produce enough insulin and the cells from insulin-responsive tissues like muscle are unable to efficiently use the insulin that is produced. The beta cells go into overdrive to try to produce insulin but become overworked and ultimately stop functioning, according to Patricia Kilian, head of the beta-cell-regeneration program at the Juvenile Diabetes Research Foundation, which partially funded the study.
Most Type 2 treatments have focused on drugs to overcome the resistance to insulin in tissues or to promote insulin output by the beta cells. But there's been a recent focus on finding ways to keep beta cells alive in the body and restoring the ability to grow new ones, Dr. Kilian says. That could help prevent or delay long-term complications of diabetes, like kidney failure and nerve damage, she says.
An early clue to CRF's role in insulin production came when Dr. Vale and a group of colleagues identified a group of hormones called urocortins about 10 years ago and later found that one of them stimulated insulin production in the pancreas. Some urocortins bind at the same receptor sites on the surface of cells that CRF does.
Recently, Dr. Vale and Mark Huising, a post-doctoral researcher, along with Nils Billestrup, a colleague at the University of Denmark, decided to see whether CRF itself might have a similar effect on beta cells. Stimulating mouse and later human beta cells with CRF, the researchers found that it not only increased insulin release but also promoted growth of the beta cells.
The next step: to learn whether CRF could stimulate insulin production in mice. This presented new challenges. Exposing the mice to CRF would trigger the production of cortisol, usually part of the stress response, which in turn boosts bloodstream sugar and so sets off the release of insulin. This response would make it difficult to figure out whether CRF or cortisol was responsible for the insulin release.
To avoid that problem, Dr. Huising inactivated the cortisol response in the mice. He then administered CRF to the pancreas of the mice and showed that it was the reason for the increased insulin production. This finding "helps us better understand how blood-sugar control works in healthy individuals and in diseases such as diabetes and obesity," says Dr. Huising.
Researchers don't know yet how to use CRF to stimulate insulin in humans without initiating the chain of stress-related events that CRF usually triggers, as well as associated effects such as increased blood pressure. And, for Type 1 diabetes, CRF would not stop the body's immune system from attacking the beta cells in the first place.
At the same time, researchers are investigating the benefits from blocking CRF. Its suppression reduces anxiety in animals, and several major drug companies are working to turn that into treatments for anxiety and depression. CRF blockers are also being developed for irritable bowel syndrome, since research has shown that stimulation of CRF receptors in the colon leads to diarrhea and pain. Also, CRF receptors in the skin might be targets for treating conditions like psoriasis, and in the bladder for overactive bladder, according to Eric Zorrilla, associate professor at the Scripps Research Institute, who studies CRF, stress and addiction.
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