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Neurology Today:
doi: 10.1097/01.NT.0000338405.10589.e8
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Researchers See Neurological Cause of Diabetes in Pancreatic Nociceptors

HURLEY, DAN

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ARTICLE IN BRIEF

Investigators propose that the major forms of diabetes, type 1 and type 2, appear to suffer from the same neurological defect and can respond to the same treatment.

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If extraordinary claims require extraordinary evidence, the researchers proposing that diabetes is fundamentally a neurological disorder appear to have both.

Flying under the radar of not only most neurologists but also of most immunologists and endocrinologists, a team from the University of Toronto has been publishing a series of studies since the turn of the millennium putting forth an audacious story: that small nerve fibers, the same type found in skin for detecting heat and other noxious stimuli, surround pancreatic beta cells and, when dysfunctional, set off the immune-system attack that results in diabetes. What's more, correcting it with an injection of the neuropeptide substance P effectively cures the disease, at least temporarily. Even more extraordinarily, they propose, both of the major forms of diabetes, type 1 and type 2, appear to suffer from the same neurological defect and can respond to the same treatment.

As described in a series of papers in prominent journals, from the Annals of Neurology to Nature Medicine, Cell, the Journal of Immunology, and Diabetes, the findings have generated equal parts excitement and puzzlement by other researchers involved in diabetes.

“Our findings were a complete surprise even to us,” said the chief architect of the theory, Hans-Michael Dosch, MD, PhD, a senior scientist at the University of Toronto who recently moved his laboratory from the department of immunology to neurosciences and mental health. Even now, after nearly a decade of published papers on the subject, he said: “People remain skeptical — there is no precedent for our work. When our institution recently sought patent protection on some of our findings, they were told, ‘The only references we can find are from some group in Toronto’—our own work.”

Yet according to a Yale researcher conducting similar research on the role of airway pain receptors in the development of asthma, the fact that few scientists involved in diabetes research understand what the Toronto team is up to is understandable.

“Science nowadays is very compartmentalized,” said Sven-Eric Jordt, PhD, an assistant professor at the Yale University School of Medicine in the department of pharmacology. “This research encompasses immunology, sensory research, pain research, and diabetes research. It's so interdisciplinary that people are having a hard time judging it. But this is honest work that has gone through a very rough peer-review process. They have made spectacular findings.”

The chief of neurosciences at the University of Toronto and a longtime collaborator on the research, Mike Salter, MD, PhD, said that even he has been surprised where their research has led them.

“I'm coming at this as a pain biologist,” Dr. Salter said. “It's been a long road that began when we were working together to show that pancreatic beta cells do have nerve fibers in them, then showing that they're nociceptors. We have just pursued one unusual finding after another.”

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A WATERSHED PAPER

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Their watershed paper, published in the Dec. 15, 2006, issue of Cell, described their efforts to explain why T lymphocytes begin attacking insulin-producing islet cells in type 1 diabetes. Working with the standard animal model, diabetes-prone NOD (non-obese diabetic) mice, they reported that sensory neurons positive for transient receptor potential vanilloid 1 (TRPV1) surround the islet cells, and that killing the neurons by injecting capsaicin results in remission of all diabetic symptoms for weeks or even months in up to 90 percent of the mice treated.

Although they naturally assumed that the nociceptors had been over-active, causing inflammation by releasing too much substance P, they found just the opposite: the nociceptors were under-active, releasing too little substance P. Delivering the neuropeptide to the mice's pancreas by intra-arterial injection reversed abnormal insulin resistance, insulitis, and diabetes for weeks to several months.

“These results suggest a clear link between autoimmunity, inflammation, and the nervous system,” stated an editorial accompanying the Cell paper, co-authored by Jeffrey A. Bluestone, director of the University of California-San Francisco's Diabetes Center. While elucidating how the paper fits with other recent findings, the editorial also raised a number of questions. Other studies, for instance, suggest that the neuronal defect identified by the Toronto team “does not fully account for the initiation of the autoimmune process in NOD mice,” the editorial stated.

Dr. Jordt agreed that not all the conclusions in the Cell paper are absolutely convincing. But, he said: “Their findings are in line with research from many other studies showing these small nerve fibers can play a role in modulating immunological function. More and more results have come out showing that these peripheral neurons that sense pain and can secrete certain messaging molecules in response to pain or stress or inflammation can actually modulate the immune response.”

Dr. Salter acknowledged that their papers have raised questions that they have yet to fully answer. “We're still trying to work out what's going on,” Dr. Salter said. “The simplest explanation is that there's an interaction between the sensory nerves and the beta cells. The nerves seem to be there to help in the care and feeding of the beta cells. If that interaction becomes abnormal, it causes the beta cells to become stressed out — and stressed out beta cells are a great target for lymphocytes.”

In papers not yet published but presented at meetings, the researchers have extended their findings to mouse models of type 2 diabetes, and even to obesity itself.

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RESPONSE FROM NEUROLOGISTS

“The reaction we get from many immunologists and others who study diabetes is incredulity,” Dr. Salter said. “They tell us there's no way this is possible. But neuroscientists know that the nervous system is involved in regulating just about every cell in our body.”

The paper in Cell drew the attention of neurologists involved in studying the neurologic complications of diabetes.

“We did a journal club on his findings,” said Christopher Gibbons, MD, of the Center for Autonomic and Peripheral Nerve Disorders at Beth Israel Deaconess Medical Center in Boston and an instructor in neurology at Harvard Medical School. “It's very provocative work. At this point, he seems to have raised more questions than answers. But my understanding of what he's done is pretty limited. I find it really fascinating, but it's out of my area of expertise, the human peripheral nervous system.”

His colleague, Clifford B. Saper, MD, PhD, the James Jackson Putnam Professor of Neurology and Neuroscience at Harvard Medical School and chairman of the department of neurology at Beth Israel Deaconess, offered an explanation for why even neurologists who are intrigued by Dr. Dosch's work do not fully understand it.

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Figure. DR. MIKE SAL...
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“It's interdisciplinary, and mostly published in diabetes journals, where it would not get much attention from neurologists or neuroscientists,” Dr. Saper said. But, he added: “There is an emerging concept that there is a CNS contribution to diabetes.”

One neuroscientist who has studied TRPV1-positive nociceptors said that research into their role in bone, organs, deep muscle tissue, and elsewhere in the body is exploding. “These small fibers regulate many endocrine functions,” said Marco Pappagallo, MD, director of pain medicine research and development and professor in the department of anesthesiology at Mount Sinai School of Medicine in New York. “They are so much more afferent messengers to the CNS. They also have efferent output with all these neuropeptides. There's a lot to learn.”

Dr. Pappagallo has co-authored papers with one of the leading international experts on capsaicin and TRPV1 receptors, Arpad Szallasi, MD, PhD, a pathologist at Monmouth Medical Center in Long Branch, NJ, and adjunct professor at Drexel University.

“I was very happy to see the Cell paper, but I wasn't taken by surprise,” Dr. Szallasi said. “It created a big splash. It is all over the Internet, generating hope that type 1 diabetes can be cured, and not only managed, in the foreseeable future. But the concept that there is a precise and delicate relationship between the immune and neurologic systems is not new. And there are aspects to their findings that are puzzling and difficult to foresee clinical applications.”

A particular point of confusion, he said, “is that both loss of substance P (by capsaicin pretreatment) and extra substance P (by direct injection into the pancreatic circulation) are beneficial in the mouse model of type 1 diabetes.”

However the confusion is resolved, he added in an e-mail: “The clinical implication for type 1 diabetes is obscure. Substance P cannot be given systematically (it evokes pain, inflammation, etc.) and I cannot visualize any practical means to directly inject it into the human endocrine pancreas.”

But in fact, Dr. Dosch said, it is injected rather easily through the pancreatic artery, and a human trial is set to begin later this year involving newly diagnosed type 1 diabetics.

The clinical implications for type 2 diabetes, Dr. Szallasi said, are more straightforward, he added. “Drugs like rimonabant (sold in the UK under the brand name Acomplia) have a proven anti-inflammatory activity and in animal models TRPV1 antagonists are clearly beneficial by improving glucose control,” he said.

In the meanwhile, “We still have surprising difficulties financing this process,” Dr. Dosch said of his pending trial of treating newly diagnosed type 1 diabetics with substance P.

The one thing certain as they investigate a neurological etiology for diabetes is that the challenge of getting funding will change. Either it will get easier, should the results of human trials prove positive, or it will become as tough as finding funding for desktop fusion.

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REFERENCES

• Tsui H, Chan Y, Tang L, et al. Targeting of pancreatic glia in type 1 diabetes. Diabetes 2008;57(4):918–928.
• Suri A, Szallasi A. The emerging role of TRPV1 in diabetes and obesity. Trends Pharmacol Sci 2008;29(1):29–36.

• Banwell B, Bar-Or A, Cheung R, et al. Abnormal T-cell reactivities in childhood inflammatory demyelinating disease and type 1 diabetes. Ann Neurol 2008 Jan;63(1):98–111.
• Razavi R, Chan Y, Afifiyan FN, et al. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell 2006;127:1123–1135.

• Bour-Jordan H, Bluestone J. Sensory neurons link the nervous system and autoimmune diabetes. Cell 2006;127:1097–1099.

• Winer S, Tsui H, Lau A, et al. Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. Nature Med 2003;9:198–205.
• Winer S, Astsaturov I, Cheung RK, et al. Type 1 diabetes and multiple sclerosis patients target islet plus nervous system autoantigens; Nonimmunized nonobese diabetes mice can develop autoimmune encephalitis. J Immunol 2001; 166:2831–2412.

• Karjalainen J, Martin JM, Knip M, et al. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. New Eng J Med 1992;327:302–307.

©2008 American Academy of Neurology

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