A group of researchers looked into the link between fatty liver disease and the key markers of type 2 diabetes in mice. What they found is that by lessening the production of neurotransmitter GABA within the liver could actually help normalize blood glucose levels, while lessening the appetite which leads to weight loss. They explain that this particular treatment could work especially with patients diagnosed with obesity.
Type 2 diabetes occurs when individuals suffer from insulin resistance for one reason or another, which then causes high blood sugar levels
Insulin is described as a hormone that aids glucose to enter one’s cells where they are either used for energy or kept for future use. When insulin resistance occurs, the cells in the body don’t respond properly to insulin and lack the ability to remove the glucose from the person’s blood.
For patients with type 2 diabetes, their insulin resistance causes an increase in the body’s ability to produce insulin. When this happens, a number of things can happen like high blood pressure, increased appetite and weight gain.
Former research has proven that type 2 diabetes is often associated with being overweight, as well as fatty liver disease, which occurs when the liver stores excess fat. Meanwhile, the Centers for Disease Control and Prevention (CDC) explain that 89% of people with diabetes are actually overweight.
Although scientists hypothesize that excess fat in the liver possibly causes type 2 diabetes, they haven’t exactly figured out how.
Just recently, research groups from the Northwestern University, University of Arizona, University of Pennsylvania, and Washington University in St. Louis decided to conduct two studies to scrutinize ‘the underlying mechanisms linking fatty liver disease with glucose homeostasis,’ which is basically the ‘balance between insulin and glucose in the blood.’
What they discovered is that insulin sensitivity can be refreshed in just a few days by lessening the over production of the neurotransmitter GABA in the liver. As a result, this type of long-term treatment could possibly bring about a decrease in weight loss and appetite.
Neurotransmitters are the links sent between the nerves which allow the brain and other portions of the body to communicate with each other. GABA is an ‘inhibitory neurotransmitter,’ which means that it lessens the signals within the nervous system.
Study author Dr. Benjamin Renquist said, “When the liver produces GABA, it decreases [the] activity of those nerves that run from the liver to the brain. Thus, fatty liver, by producing GABA, is decreasing firing activity to the brain. That decrease in firing is sensed by the central nervous system, which changes outgoing signals that affect glucose homeostasis.”
The study can be found published in the medical journal Cell Reports.
Looking At the Mouse Studies
What the researchers first found out from studying the mice is that ‘obesity-induced fatty liver disease increases the production of GABA in the liver.’ Afterwards, they found out that ‘increased GABA signaling from the liver affects glucose homeostasis.’
While earlier research discovered that the GABA transaminase enzyme (GABA-T) happens to be the trigger to produce GABA in the liver, they figured that by ‘targeting GABA-T to produce less GABA in the liver may reduce insulin resistance and treat type 2 diabetes.’
In order to test their hypothesis, the research group first ‘treated mouse models of type 2 diabetes with drugs that inhibit GABA-T activity.’ These medications are called ethanol-amine-O-sulfate (EOS) and vigabatrin.
Then, the researchers second way of testing their hypothesis used a genetic treatment called antisense oligonucleotide(ASO). How this works is that it binds small pieces of RNA or DNA to molecules of RNA to stop them from creating particular proteins. They shared that in this case, the ASO worked by ‘disabling GABA-T expression in the liver.’
The scientists also shared how both treatment methods were successful at reducing the GABA-T activity while improving the insulin sensitivity in a matter of days. The mice that were given ASO and EOS drugs also managed to lose 20% of their body mass just seven weeks after their treatment first began.
Researchers then analyzed liver samples from 19 obese people during their bariatric surgery procedures. They also examined the gene expression in the liver tissue, where they found that the people with insulin resistance also had ‘high levels of expression for genes related to GABA production and activity.’
And what this means is that the results found in the mouse models could possibly translate to humans too.
The Exclusive Results For Obesity
To further explain their outcome, the scientists shared that excess fat in the liver does increase the release of GABA, and as a result it ‘suppresses the firing of the hepatic vagal afferent nerve,’ which works as a communication connection between the brain and the liver.
The researchers explain that by suppressing this nerve using GABA, which is also done using other appetite regulators, it increases food intake and therefore, weight gain, which then increases insulin resistance. So by letting the nerve work as normal, it does the opposite by lessening food intake, reducing weight gain and lowering insulin resistance.
The team also tested out their GABA-T inhibitory methods on non-obese mice. Since they were considered to have low levels of GABA production in their livers, the medications had very slight to zero effects on their insulin levels, blood sugar levels, and body mass as well.
What the research group concluded is that by targeting GABA production in the liver, it could improve ‘glucose homeostatis, decrease food intake, and reduce body mass’ exclusively for those suffering from obesity.
Dr. Renquist shares, “All current therapeutics for type 2 diabetes primarily aim to decrease blood glucose. So, they are treating a symptom, much like treating the flu by decreasing the fever,” adding, “We need another breakthrough.”
He goes on to say, “A novel pharmacological target is just the first step in application; we are years away from anything reaching the neighborhood pharmacy. […]The magnitude of the obesity crisis makes these promising findings an important first step that we hope will eventually impact the health of our family, friends, and community.”
While not affiliated with the study, according to head of the research communications at Diabetes UK to Medical News Today, Dr. Lucy Chambers, “While these findings won’t change treatment options in the short-term, they give scientists a new avenue for the development of new treatments such as GABA inhibitors, which could, in [the] future, help reduce the release of GABA in the liver, potentially offering a new way for people with type 2 diabetes to manage their condition.”
She also shared with MNT, “While this study was robust, it’s important to note that it was carried out in mouse models of type 2 diabetes and obesity. Additional human studies are now needed to explore the link between liver GABA production and insulin sensitivity and food intake further.”
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