JANUARY 15, 2007


Canadian team cracks type I diabetes code

Targeting defective neurons could lead to a cure for types I and II

Canadian researchers may well have just cracked the root cause of type I diabetes, opening up new avenues of treatment, prevention and potential cure for this baffling disease. What's more, the findings could have major implications for the more prevalent type II diabetes — maybe even other autoimmune pathologies as well.

The astonishing results — though only seen in mice so far — seem to have overturned the longstanding assumption that type I diabetes is caused by a defect in immune cells. The cells that are actually responsible for the pathogenesis of the disease are sensory nerve cells in the pancreas called TRPV1 neurons, researchers from the Toronto Hospital for Sick Children and the University of Calgary reported in the journal

on December 15. With that understanding, they succeeded in reversing the disease without any serious immunosuppressive side effects.

It's well known that diabetes involves a progressive failure of the insulin-producing cells in the pancreatic islets of Langerhans. The stress and death of these cells attracts autoantigens that in turn draw in lymphocytes, which attack the remaining cells. But those same autoantigens are also present elsewhere in the body, and despite decades of research, it remained unclear why such a severe autoimmune reaction occurred only in the pancreas — until now.

"We started to look at nervous system elements that seemed to play a role in type I diabetes and found that specific sensory neurons are critical for islet immune attack in the pancreas," Dr Hans Michael Dosch, the study's principal investigator and senior scientist at the Toronto Hospital for Sick Children, explained in a release.

What's more, the nerves' own function is dependent on local insulin levels: in the absence of sufficient insulin, they produce less of the neuropeptide known as substance P. Lack of substance P, the researchers hypothesised, in turn harms cell function, further reducing insulin production.

To test their theory, the team destroyed TRPV1 neurons by injecting capsaicin into the pancreas of non-obese diabetic (NOD) mice — the mainstay model of diabetes research. Capsaicin (present in hot peppers) is known to specifically target the neurons, leaving the surrounding tissue untouched.

At 20 weeks' age, more than 70% of the islets were completely free of infiltration by lymphocytes — a hugely significant reduction in autoimmune inflammation. Capsaicin treatment delayed the onset of diabetes and reduced its final incidence by about 80%.

Eliminating the sensory neurons in a mouse model certainly seemed to prevent diabetes, but its applicability to human treatment might be questionable, the researchers knew. After all, destroying neurons in newborn children on the off chance that they might otherwise develop type I diabetes is likely to raise some eyebrows.

"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," said Dr Dosch. Starting in the next few months, he hopes to look for sensory abnormalities in children born to families at high-risk of type I diabetes, and to follow them in order to identify a connection to disease onset.

In the meantime, there's another even more promising avenue to explore. The researchers also discovered that injecting substance P, the neuropeptide whose production is impaired in faulty pancreatic sensory neurons, produced equally startling results. Injected into the pancreatic artery of diabetic mice, it caused the disease to simply disappear in more than half of them, for periods ranging from two weeks to two months. Insulin resistance fell and blood glucose levels were normalized. Even in the mice whose diabetes remained, metabolic control improved and the weight loss typical in diabetic NOD mice was avoided.

Buoyed by their findings, the researchers extended their study to type II diabetes, a much more prevalent form of the disease where insulin resistance is even more pronounced. They compared mice of the B6 strain, a model of type II diabetes, with and without expression of TRPV1. Sure enough, the latter group showed much better glucose response after glucose challenge, suggesting that TRPV1 may play a role in type II disease as well.

And that's just the start of it. The mutant gene that causes the TRPV1 defect in the NOD mouse is located on a stretch of DNA called the Idd4 diabetes risk locus. There's reason to believe that risk loci associated with other autoimmune diseases overlap with this snippet, raising the possibility that TRPV1 might play a role in more than just diabetes.

Collaborator Dr Pere Santamaria of the University of Calgary said the implications could be monumental. "This discovery opens up an entirely new field of investigations in type I and possibly type II diabetes, as well as tissue selective autoimmunity in general. We have created a better understanding of both type I and type II diabetes, with new therapeutic targets and approaches derived for both diseases."



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