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Research at the Hospital for Sick Children in Toronto may have revealed a fundamental mechanism underlying the cause of diabetes—and perhaps a novel target for treatment.
According to traditional thinking, type 1 diabetes is an autoimmune disorder of the pancreas. Inflamed and under assault by T-cells, beta cells are destroyed along with the body's source of insulin.
Investigators found evidence that the autoimmune attack on beta cells appears to be triggered by abnormal sensory nerves that lack a neuropeptide, substance P.
Studies of nonobese diabetic mice found that their sensory neurons did not produce enough substance P. When these mice were given an injection of substance P directly into the pancreas, insulin and glucose levels returned to normal. The findings were reported in a recent issue of the journal Cell.1
"We are extremely excited about this," says Hans Michael Dosch, MD. "It comes totally out of left field. We had no idea where we'd end up when we embarked on this."
HOT ON THE TRAIL
Previously, Dosch and colleagues observed that inflammation affects not only islet cells in type 1 diabetes, but nearby sensory neurons as well. Inflammation of the nerves—as in peripheral and retinal neuropathy—has long been associated with diabetes. But it's always been assumed to be a result of the disease and not the cause.
The group, as well as other investigators, believes that a control circuit between neurons and pancreatic cells regulates the production of insulin. "In diabetes-prone mice, these nerves play a critical role in diabetes development," says Dosch.
Studies revealed that the sensory nerves in the pancreas were rich in neurokinin receptor NK1, which binds with substance P.
Substance P is a neuropeptide associated with heat, pain, and noxious sensation. Capsaicin—the pungent substance found in red pepper—triggers the release of substance P. Repeated exposure to capsaicin depletes substance P from nerve endings, resulting in analgesia.
However, according to an emerging theory, substance P plays a much more critical role in pancreatic health and the production of insulin. "In the pancreas, substance P is a critical well-being factor," says Dosch. "It's like red wine for beta cells."
If substance P works in humans as it does in mice, a single injection may resolve the signs and symptoms of diabetes for 6–12 months. Whether the compound can make that leap remains to be seen.
The NK1 receptor to which substance P binds is a notoriously elusive target. A compound that acts on the same receptor could have considerable commercial value as an analgesic. However, drug companies have found the area fraught with difficulties for development.
"Drug development [with the NK1 receptor] hasn't been successful," says Dosch. "This is our biggest concern."
Dosch and colleagues are continuing the line of research by looking for evidence of diabetes-related sensory nerve disorders in humans and are planning clinical trials to evaluate injections of substance P or capsaicin.
Regardless of the outcome, the research has added a tantalizing piece to
the scientific puzzle of the causes of diabetes. 
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| DOC News | Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |
