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.
A
NERVOUS BREAKDOWN
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%.
FROM
MICE TO MEN
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.
BEYOND
TYPE I
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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