Obesity is currently on the rise, along with a related increase in the incidence of type 2 diabetes. A hundred years after the discovery of insulin, new approaches are needed to address this global public health crisis.

Researchers at the University of Arizona (UA) believe the liver may hold the key to innovative new treatments. “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,” says Benjamin Renquist, PhD, associate professor in the UA College of Agriculture and Life Sciences and BIO5 Institute member. “We need another breakthrough.”

Benjamin Renquist, PhD, is associate professor at the UA College of Agriculture and Life Sciences and BIO5 Institute member

Renquist, along with collaborating scientists from Washington University in St. Louis, the University of Pennsylvania and Northwestern University, outline a new target for Type 2 diabetes treatment in two new papers in Cell Reports,”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 team focuses on better understanding the links between obesity, fatty liver disease and diabetes, particularly how the liver affects insulin sensitivity.

“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 Renquist. “As fat increases in the liver, the incidence of diabetes increases.” But how fat in the liver could cause the body to become resistant to insulin or cause the pancreas to over-secrete insulin remained a mystery.

Measuring neurotransmitters released from the liver in animal models of obesity, Renquist’s team attempted to understand how the liver communicates with the brain to impact metabolic shifts associated with obesity and diabetes.

“We found that fat in the liver increased the release of the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA,” says Renquist. “We then identified the pathway by which GABA synthesis was occurring and the key enzyme that is responsible for liver GABA production—GABA transaminase.” GABA is the primary inhibitory neurotransmitter in the central nervous system, that reigns in excitatory neural activity.

The communication between the brain and the body is a two-way street. Just as the brain sends neural messages to the body, similar messages are also transmitted from the body to the brain.

“When the liver produces GABA, it decreases 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,” says Renquist. “That decrease in firing is sensed by the central nervous system, which changes outgoing signals that affect glucose homeostasis.”

Caroline Geisler and Susma Ghimire, graduate students in Renquist’s lab, pharmacologically inhibited liver GABA transaminase in animal models of Type 2 diabetes to see if increased liver GABA synthesis was causing insulin resistance.

Caroline Geisler, PhD, graduate student in Renquist’s lab and now postdoctoral researcher at the University of Pennsylvania, is lead author on both papers.

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

Kendra Miller, a research technician in Renquist’s lab, identified variations in the genome near GABA transaminase that were associated with Type 2 diabetes in a quest to ascertain whether the animal model findings would translate to humans. Collaborating with investigators at Washington University, the researchers show individuals with insulin resistance express higher levels of enzymes that synthesize and release GABA from liver cells.

“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,” says Renquist.

In a clinical trial (NCT04321395) funded by the Arizona Biomedical Research Commission and 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, the researchers are investigating the use of a commercially available GABA transaminase inhibitor, Vigabatrin, to improve insulin sensitivity in people who are obese.

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