Researchers at The Hospital for Sick Children (SickKids), the University of Calgary and The Jackson Laboratory, Bar Harbor, Maine have found that diabetes is controlled by abnormalities in the sensory nociceptor (pain-related) nerve endings in the pancreatic islet cells that produce insulin. This discovery, a breakthrough that has long been the elusive goal of diabetes research, has led to new treatment strategies for diabetes, achieving reversal of the disease without severe, toxic immunosuppression.
When the mice’s pancreatic sensory nerves were injected with the substance, they began producing insulin normally almost instantaneously. Trials on humans with type one and type two diabetes are expected to begin within the next six months.

One of the doctors leading the research, Michael Dosch, said that with similar results in humans, one injection could keep diabetes at bay for years. Dosch described the research as “stunning”. Christian Stohler of the University of Maryland, who reviewed the research, said it opened “a novel, exciting door to address one of the diseases with large societal impact”.

The researchers also concluded that type one and type two diabetes are more alike than previously thought and found that nerves can play a role in other chronic inflammatory conditions such as inflammatory bowel disease and asthma.

Type 1 diabetes is an autoimmune disorder that affects more than ten per cent of the 21 million diagnosed with diabetes. Studies have focused on the immune system as the sole offender and research into the fundamental mechanisms of the disease have been overdue. Pancreatic islet cells, the cells responsible for the production of pancreatic hormones such as insulin, play a key role in the disease. In diabetes, islets become inflamed and are ultimately destroyed, making insulin production impossible. Insulin deficiency is fatal and current insulin replacement therapies cannot prevent many side effects such as heart attacks, blindness, strokes, loss of limbs and kidney function.

The SickKids research group has long been pursuing links between diabetes and the nervous system, studying both humans and animal models of the disease. Recently, the group found an unsuspected control circuit between insulin-producing islets and their associated sensory or pain nerves. This circuit sustains normal islet function.

“We started to look at nervous system elements that seemed to play a role in Type 1 diabetes and found that specific sensory neurons are critical for islet immune attack in the pancreas,” said Dr. Hans Michael Dosch, study principal investigator, senior scientist at SickKids and professor of Paediatrics and Immunology at the University of Toronto. “These nerves secrete insufficient neuropeptides which sustain normal islet function, creating a vicious circle of progressive islet stress.”

Using diabetes-prone NOD mice, the gold-standard diabetes model, the research group learned how to treat the abnormality by supplying neuropeptides and even reversed established diabetes.

“The major discovery was that removal of sensory neurons expressing the receptor TRPV1 neurons in NOD mice prevented islet cell inflammation and diabetes in most animals, which led us to fundamentally new insights into the mechanisms of this disease,” said Dr. Michael Salter, co-principal investigator, senior scientist at SickKids, professor of Physiology and director of the Centre for the Study of Pain at the University of Toronto. “Disease protection occurred despite the fact that autoimmunity continues in the animals. This helped us to focus our studies on finding the new control circuit in the islets.”

Strikingly, injection of the neuropeptide substance P cleared islet inflammation in NOD mice within a day and independently normalized the elevated insulin resistance normally associated with the disease. The two effects synergized to reverse diabetes without severely toxic immunosuppression.

The studies were extended to Type 2 (obesity-associated) diabetes, in which insulin resistance is even more severe, using a number of additional model systems, thus generating strong evidence that treating the islet-sensory nerve circuit can work to dramatically normalize insulin resistance in models of Type 2 diabetes.

“This discovery opens up an entirely new field of investigations in Type 1 and possibly Type 2 diabetes, as well as tissue selective autoimmunity in general,” said Dr. Pere Santamaria, study collaborator and professor of Microbiology and Infectious Diseases at the University of Calgary. “We have created a better understanding of both Type 1 and Type 2 diabetes, with new therapeutic targets and approaches derived for both diseases.”

“We are now working hard to extend our studies to patients, where many have sensory nerve abnormalities, but we don’t yet know if these abnormalities start early in life and if they contribute to disease development,” added Dosch.
This research is reported in the December 15 issue of the journal Cell.

====================================================

Advertisement:
Breaking News from the American Diabetes Association 66th Scientific Sessions
Did you miss the ADA Scientific Sessions in Washington, DC? Get up to speed on the latest research and updates to current knowledge on diabetes and dyslipidemia-FREE CME Activities from the ADA Scientific Sessions are now available! Click here to access the interactive CME newsletter summary of several presentations relevant to clinical practice and the CME case-based slide and audio presentations on the real-world management of patients with diabetes and dyslipidemia recorded at the ADA meeting. Don't miss this opportunity to learn the latest clinical updates from one of the year's most critical diabetes events!
http://www.cemedicus.com/diabetes