http://www.physorg.com/news126965682.html

Potential drug target identified for diabetes by studying novel
gut-brain-liver circuit

Scientists at the Toronto General Hospital Research Institute have
discovered a novel signaling pathway between three organs - the gut, the
brain, and the liver - which lowers blood sugar when activated.

A team led by Dr. Tony Lam used a rat model to discover that fats can
activate a subset of nerves in the intestine, which then send a signal to
the brain and subsequently to the liver to lower glucose or sugar
production. But eating a high-fat diet for just three days can interfere
with this signal, disabling it so that it does not signal the other organs
to lower blood glucose levels.

The research was published in a paper entitled, "Upper intestinal lipids
trigger a gut-brain-liver axis to regulate glucose production" as an advance
on-line publication of the international science journal Nature.

"This is a new approach in developing more effective methods to lower
glucose or blood sugar levels in those who are obese or have diabetes," said
Dr. Lam, who holds The John Kitson McIvor (1915 - 1942) Chair in Diabetes
Research at the University Health Network and University of Toronto.
Currently, those with diabetes lower their glucose through diet, exercise,
anti-diabetic tablets or insulin injections (usually several times a day)
and must regularly monitor blood glucose levels. High glucose levels can
result in damage to eyes, nerves and kidneys and increase the risk of heart
attack, stroke, blindness, erectile dysfunction, foot problems and
amputations. Many laboratories around the world are in a race to find
alternative and effective ways in which to lower glucose levels because of
the severe complications which can result from high sugar levels.

"We already knew that the brain and liver can regulate blood glucose levels,
but the question has been, how do you therapeutically target either of these
two organs without incurring side effects?" noted Dr. Lam, who is also an
Assistant Professor of Physiology and Medicine at the University of Toronto.
"We may have found a way around this problem by suggesting that the gut can
be the initial target instead. Much like a remote control device, the gut is
able to relay a signal to the brain which in turn signals the liver to lower
glucose production. If new medicines can be developed that stimulate this
sensing mechanism in the gut, we may have an effective way of slowing down
the body's production of sugar, thereby lowering blood sugar levels in
diabetes."

Dr. Lam emphasized that it will take a number of years of experimental work
to determine whether this approach is effective and safe in humans who have
diabetes.

More than two million Canadians have diabetes. "Diabetes is an epidemic in
Canada and around the world and its numbers are continuing to increase at an
alarming rate, consuming our precious health care resources," says Dr. Gary
Lewis, Head of the Division of Endocrinology and Metabolism at the
University Health Network and Mount Sinai Hospitals in Toronto and Professor
of Medicine and Physiology at the University of Toronto. "We have good
evidence from clinical trials which shows that lowering blood glucose levels
towards normal in those who develop diabetes has a major impact in
preventing its devastating complications, so it is critical that we learn
how to control these levels in the most effective and least invasive ways
possible. Dr. Lam's work reveals a new regulatory circuit which provides
novel sites and targets to lower these levels in diabetes and obesity."

Dr. Richard Weisel, Director of the Toronto General Research Institute
(TGRI), Professor and Chairman of Cardiac Surgery at the University of
Toronto, welcomes any potential interventions which can help lower blood
sugar levels. "Studies have shown that people with very high blood glucose
levels are more likely to die from heart disease, so anything that we can
discover to help lower these levels would help in decreasing the progression
of and mortality from cardiovascular disease."

"Tony's discovery represents an exciting breakthrough that could eventually
lead to new ways to treat diabetes," observed Dr. Diane Finegood, Scientific
Director of the Institute of Nutrition, Metabolism and Diabetes, part of the
Canadian Institutes of Health Research (CIHR). "I am pleased that CIHR
played a major role in funding this research".

Working with rats, Dr. Lam and colleagues designed and performed a series of
elegant experiments which showed for the first time that the lipids or fats
which enter the small intestine trigger the afferent neuronal signal to the
brain which then sends signals to the liver to lower glucose production and
blood glucose levels in as little as fifteen minutes. No drop in levels
occurred when nerves were cut or blocked between the gut and the brain or
between the brain and the liver. The trigger to lower glucose was also
disabled when rats were fed a high-fat diet for three days prior to the
experiment, a finding which may suggest that those who eat a high fat diet
lose this beneficial signaling pathway.

Source: Canadian Institutes of Health Research