A University of Arizona study on Type 2 diabetes could completely alter the way the disease is treated by fighting it a different way.
While nearly every treatment addresses the complications caused by Type 2 diabetes, namely the dangerously high levels of glucose in the bloodstream, these scientists’ findings indicate the disease could be fought at its source: the way the liver communicates with the rest of the body.
Benjamin Renquist, an associate professor at the UA and principal investigator for this study, said he essentially stumbled upon the discovery by accident while conducting a study to determine a correlation between hunger and fat buildup in the liver.
“That’s kind of science all the time,” Renquist said. “It’s very rarely a straight road, so you just have to be willing to take the turn when you find it.”
The key to these new findings is a neurotransmitter — a signal in the body that sends information to the brain — produced in the liver and known as GABA, short for gamma aminobutyric acid.
“We know there’s a nerve that runs from the liver to the brain,” Renquist said. “And we showed that if we cut that nerve, we improved insulin sensitivity in obese mice.”
The team of researchers discovered that GABA, when produced in high quantities due to fat buildup in the liver, may be behind the insulin resistance that characterizes Type 2 diabetes and causes the high blood glucose levels, he said.
Inhibiting GABA production, release or its communication with the brain would then prevent the development of an insulin resistance, said Caroline Geisler, who worked on the study as a UA animal studies doctorate student up until her graduation in 2019.
According to Renquist, Geisler realized inhibiting GABA production would be different from other Type 2 diabetes treatments in that it would address the root of the problem, not just symptoms.
The study also showed promising results for weight loss.
“We’re causing weight loss because we’ve identified the (hunger) signal produced by the liver that tells the rest of the body you’re in an energy deficit state,” Renquist said.
While there are already GABA-inhibiting drugs available, they are primarily meant to treat epilepsy, meaning they affect the brain, and wouldn’t be suitable for use in patients with diabetes, he said.
“We are developing inhibitors that won’t cross into the brain and are specific for the peripheral tissues, specifically the liver,” Renquist said.
One undergraduate researcher involved in the study, Jason Kronenfeld, tested thousands of compounds on their ability to inhibit the release of GABA, compounds that could eventually be used in drugs designed to treat Type 2 diabetes.
Kronenfeld, who worked on various projects with the team throughout his undergraduate career until he graduated this spring, summarized his results in his honors thesis.
He said he identified 71 compounds that inhibited GABA production, which he then narrowed to four that will now go through further testing funded by Tech Launch Arizona.
Type 2 diabetes is linked to obesity, which causes a buildup of fat in the liver. Beyond causing high blood sugar, diabetes is also the leading cause of amputations in the U.S. and is associated with higher risks of developing cancer.
With almost 30% of Arizonans being obese, 10% being diabetic and 9% prediabetic, according to the Arizona Department of Health Services, Type 2 diabetes is a problem very close to home.
“All of us have family members who have struggled with body-weight regulation and preventing obesity, or friends that have that same issue, and so I think every Arizonan could be touched by a novel therapeutic,” Renquist said.
While a drug harnessing these research findings won’t be immediately available, Renquist said in the best-case scenario, GABA inhibitors designed for diabetes patients could be available within five to seven years.