Type 2 Diabetes and Linked Obesity is Prevented by identified Liver Target

Obesity is on the rise, as is the incidence of type 2 diabetes that goes along with it. New measures are needed to solve the global public health challenge a century after the discovery of insulin.

According to University of Arizona (UA) researchers, liver may hold the key to novel new treatments. “The primary goal of all current Type 2 diabetes treatments is to lower blood glucose levels. As a result, they are treating a symptom, similar to how the flu is treated by lowering the fever,” explains by Benjamin Renquist, PhD, associate professor in the UA College of Agriculture and Life Sciences and member of the BIO5 Institute stated  “Another breakthrough is required.”

In two new papers published in Cell Reports, Renquist, along with collaborators from Washington University in St. Louis, the University of Pennsylvania, and Northwestern University, outline a new target for Type 2 diabetes treatment.

Papers titled "A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity” and “Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release.” Renquist's group is interested in learning more about the connections between obesity, fatty liver disease, and diabetes, specifically how the liver influences insulin sensitivity.

“Obesity is recognized to be a cause of Type 2 diabetes, and we've known for a long time that obesity increases the amount of fat in the liver,” Renquist says. “As the amount of fat in the liver increases, so does the risk of diabetes.” But it was unclear how fat in the liver could make the body resistant to insulin or cause the pancreas to oversecrete insulin.

Renquist's team aimed to understand how the liver communicates with the brain to influence metabolic alterations linked with obesity and diabetes by measuring neurotransmitters released by the liver in animal models of obesity.

Renquist explains, "We discovered that fat in the liver boosted the release of the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA." “We then discovered the GABA manufacturing pathway and the crucial enzyme GABA transaminase, which is responsible for liver GABA production.” In the central nervous system, GABA is the principal inhibitory neurotransmitter that controls excitatory neuronal activity.

It's a two-way street when it comes to communication between the brain and the body. Similar messages are sent from the body to the brain, just as the brain sends neural messages to the body.

“When the liver produces GABA, the activity of nerves that travel from the liver to the brain is reduced. As a result, fatty liver reduces brain firing activity via generating GABA, according to Renquist. “The central nervous system detects the decrease in firing and modifies outgoing signals that affect glucose homeostasis.”

Graduate students in Renquist's lab Caroline Geisler and Susma Ghimire pharmacologically suppressed liver GABA transaminase in animal models of Type 2 diabetes to test if increased liver GABA production caused insulin resistance.

Geisler, now a postdoctoral researcher at the University of Pennsylvania and main author on the articles, adds that inhibiting excess liver GABA production restored insulin sensitivity within days. “Longer-term inhibition of GABA-transaminase resulted in weight loss and decreased food intake.”

In order to see if the animal model findings would apply to people, Kendra Miller, a research worker in Renquist's lab, uncovered polymorphisms in the genome near GABA transaminase that were connected with Type 2 diabetes. In collaboration with Washington University academics, the researchers discovered that people who are insulin resistant have higher levels of enzymes that produce and release GABA from liver cells.

“Given the scope of the obesity issue, these hopeful findings are a vital first step toward improving the health of our family, friends, and community,” Renquist adds.

The researchers are investigating the use of a commercially available GABA transaminase inhibitor,, in a clinical trial (NCT04321395) currently underway at Washington University School of Medicine in St. Louis with collaborator Samuel Klein, MD, co-author on the study and a Washington University professor of medicine and nutritional science.