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

Related stories:

Life-extending protein can also have damaging effects on brain cells
Proteins widely believed to protect against aging can actually cause oxidative damage in mammalian brain cells, according to a new report in the July Cell Metabolism, a publication of Cell Press. The findings suggest that the proteins can have both proaging and protective functions, depending on the circumstances, the researchers said.
Post-exercise caffeine helps muscles refuel
Recipe to recover more quickly from exercise: Finish workout, eat pasta, and wash down with five or six cups of strong coffee.
A single mechanism for hypertension, insulin resistance and immune suppression
Many of the 75 million Americans with essential hypertension also develop diabetes and other complications in addition to their high blood pressure, and researchers have discovered a common molecular mechanism in a strain of rat that explains why such metabolic disorders arise together in mammals.
Common cooking spice shows promise in combating diabetes and obesity
Shown to reverse inflammation associated with obesity and improves blood sugar control
Turmeric, an Asian spice found in many curries, has a long history of use in reducing inflammation, healing wounds and relieving pain, but can it prevent diabetes? Since inflammation plays a big role in many diseases and is believed to be involved in onset of both obesity and Type 2 diabetes, Drew Tortoriello, M.D., an endocrinologist and research scientist at the Naomi Berrie Diabetes Center at Columbia University Medical Center, and his colleagues were curious what effect the herb might have on diabetic mice.
Lifestyle can alter gene activity, lead to insulin resistance
A Finnish study of identical twins has found that physical inactivity and acquired obesity can impair expression of the genes which help the cells produce energy. The findings suggest that lifestyle, more than heredity, contributes to insulin resistance in people who are obese. Insulin resistance increases the chance of developing diabetes and heart disease.
Hearing loss is common in people with diabetes
Hearing loss is about twice as common in adults with diabetes compared to those who do not have the disease, according to a new study funded by the National Institutes of Health (NIH).
Some patients may not need insulin for long-term control of type 2 diabetes
Some patients with type 2 diabetes can control their disease for years yet avoid insulin injections by using multiple classes of oral diabetic medications, a new study found. The results were presented Sunday, June 15, at The Endocrine Society's 90th Annual Meeting in San Francisco.
Flat carbonated drinks not an effective alternative to oral rehydration solution
‘Flat’ carbonated drinks should not be used as an alternative for oral rehydration solution to prevent dehydration in children with acute vomiting and diarrhoea, according to advice published in the May issue of Archives of Disease in Childhood.

News discussion:

Medicine & Health news