Type 2 diabetes is characterized by high blood sugar levels caused by insulin resistance.
Insulin is a hormone that helps glucose enter cells, where it can be used for energy or stored for future use. Insulin resistance happens when cells in the body do not respond well to insulin and thus do not remove glucose from the blood.
Previous research has shown that type 2 diabetes is strongly linked to
While scientists have long suspected that excess fat in the liver might cause type 2 diabetes, exactly how this could be has remained a mystery.
Recently, researchers from the University of Arizona, Washington University in St. Louis, the University of Pennsylvania, and Northwestern University conducted two studies to piece apart the underlying mechanisms linking fatty liver disease with glucose homeostasis, which is the balance between insulin and glucose in the blood.
They found that insulin sensitivity can be restored within days of reducing excess production of the neurotransmitter GABA in the liver and that long-term treatment may lead to decreased appetite and weight loss.
Neurotransmitters are sent between nerves to allow the brain and different parts of the body to communicate. GABA is an inhibitory neurotransmitter, meaning that it decreases signaling in the nervous system.
“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,” explained study author Dr. Benjamin Renquist. “That decrease in firing is sensed by the central nervous system, which changes outgoing signals that affect glucose homeostasis.”
The researchers have published their findings in Cell Reports.
From studying mice, the researchers first found that obesity-induced fatty liver disease increases the production of GABA in the liver. They then found that increased GABA signaling from the liver affects glucose homeostasis.
Because earlier research found that an enzyme called GABA transaminase (GABA-T) is key for producing GABA in the liver, the team suspected that targeting GABA-T to produce less GABA in the liver may reduce insulin resistance and treat type 2 diabetes.
To test their hypothesis, the researchers first treated mouse models of type 2 diabetes with drugs that inhibit GABA-T activity. These drugs are known as ethanol-amine-O-sulfate (EOS) and vigabatrin.
The team’s second means of testing its hypothesis involved a genetic treatment known as antisense oligonucleotide (ASO). This works by binding small pieces of DNA or RNA to molecules of RNA to stop it from making certain proteins. In this case, ASO worked by disabling GABA-T expression in the liver.
Both treatment methods reduced GABA-T activity and improved insulin sensitivity within days. Mice given ASO and EOS drugs also lost 20% of their body mass after 7 weeks of beginning treatment.
The researchers then examined liver samples taken from 19 people with obesity during bariatric surgery procedures. They analyzed gene expression in the liver tissue and found that those with insulin resistance had high levels of expression for genes related to GABA production and activity.
This means that the findings in the mouse models might translate to humans.
To explain their results, the researchers say that excess fat in the liver increases the release of GABA, which then suppresses the firing of the hepatic vagal afferent nerve, a line of communication between the liver and the brain.
Suppression of this nerve with GABA, they explain, as seen in other appetite regulators, increases food intake and weight gain, which goes on to increase insulin resistance. Allowing this nerve to fire as normal has the inverse effect of reducing food intake, weight gain, and insulin resistance.
The researchers also tested GABA-T inhibitory methods on lean mice. As these mice already had low levels of GABA production in their livers, the drugs had little to no effect on their insulin levels, blood sugar, and body mass.
The researchers conclude that targeting GABA production in the liver may improve glucose homeostasis, decrease food intake, and reduce body mass — exclusively among those with obesity.
“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,” Dr. Renquist explains, adding, “We need another breakthrough.”
“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,” he notes.
“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,” Dr. Lucy Chambers, the head of research communications at Diabetes UK, who was not involved in the study, told Medical News Today.
“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.”