Researchers investigating new diabetes treatments believe they have found evidence indicating excess production of a key neurotransmitter in the liver could be a key causal factor in the onset of insulin resistance. The discovery points to novel preventative treatments for type 2 diabetes.
"Obesity is known to be a cause of type 2 diabetes and, for a long time, we have known that the amount of fat in the liver increases with obesity," says Benjamin Renquist, a University of Arizona researcher working on the project. "As fat increases in the liver, the incidence of diabetes increases."
The link between fat in the liver and diabetes has been known for decades but it has been a mystery exactly how the liver could play a role in insulin sensitivity. The new research focused on Gamma-aminobutyric acid, or GABA, which is an inhibitory central nervous system neurotransmitter. High GABA production decreases nerve activity, and it is through this mechanism the researchers hypothesize the liver influences blood glucose levels.
"When the liver produces GABA, it decreases activity of those nerves that run from the liver to the brain,” explains Renquist. “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."
GABA production in the liver is governed by an enzyme called GABA transaminase. The researchers blocked production of this enzyme in type 2 diabetes animal models to test whether the mechanism played a role in insulin resistance.
"Inhibition of excess liver GABA production restored insulin sensitivity within days," says Carolin Geisler, lead author on two new research papers covering the novel findings. "Longer term inhibition of GABA-transaminase resulted in decreased food intake and weight loss."
Confirming these findings in humans, the researchers looked at GABA-related gene activity in subjects with type 2 diabetes. An association was detected between insulin resistance and increased expression of genes in the liver known to play a role in GABA production.
GABA transaminase inhibitors already exist, primarily designed in the past as anticonvulsant medications. A clinical trial is now underway investigating whether one of these already approved GABA transaminase inhibitors can improve insulin sensitivity in obese subjects.
Renquist says these trials are more about understanding the role this particular pathway could play in type 2 diabetes instead of proving these pre-existing drugs can be repurposed. If this liver-GABA mechanism does influence the onset of type 2 diabetes then it will direct researchers toward more specific, potentially preventative treatments.
"A novel pharmacological target is just the first step in application; we are years away from anything reaching the neighborhood pharmacy," adds Renquist. "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."
The new studies were published in the journal Cell Reports (1), (2).
Source: University of Arizona
