The liver, according to researchers, may hold the key to new, preventative Type 2 diabetes treatments. This year marks the 100th anniversary of the discovery of insulin, a scientific breakthrough that transformed Type 1 diabetes, formerly known as juvenile diabetes or insulin-dependent diabetes, from a fatal disease to a treatable condition.
Type 2 diabetes is now 24 times more common than Type 1. According to University of Arizona researchers, the rise in obesity rates and the incidence of Type 2 diabetes are linked and necessitate new approaches. The liver may hold the key to innovative new treatments.
“All current treatments for Type 2 diabetes are primarily aimed at lowering blood glucose levels. So they are treating a symptom, similar to how they treat the flu by lowering the fever” said Benjamin Renquist, an associate professor in the University Of Arizona College Of Agriculture and Life Sciences and a member of the BIO5 Institute. “Another breakthrough is required.”
Renquist and colleagues 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 published in Cell Reports.
Type 2 diabetes is 24 times more prevalent than Type 1. Researchers believe the liver may hold the key to new, preventative Type 2 diabetes treatments.
Renquist, whose research lab focuses on obesity-related diseases, has spent the last nine years trying to better understand the link between obesity, fatty liver disease, and diabetes, specifically how the liver affects insulin sensitivity.
“Obesity is known to be a cause of Type 2 diabetes, and we’ve known for a long time that the amount of fat in the liver increases with obesity,” Renquist explained. “As the amount of fat in the liver increases, so does the risk of diabetes.”
This suggested that fat in the liver could be causing Type 2 Diabetes, but how fat in the liver could cause the body to become insulin resistant or the pancreas to over-secrete insulin remained unknown, according to Renquist.
Renquist and his colleagues concentrated on fatty liver, measuring neurotransmitters released from the liver in obesity animal models to better understand how the liver communicates with the brain to influence metabolic changes seen in obesity and diabetes.
Renquist explained, “We discovered that fat in the liver increased the release of the inhibitory neurotransmitter Gamma-aminobutyric acid, or GABA.” “We then discovered the pathway by which GABA synthesis occurs, as well as the key enzyme responsible for GABA production in the liver, GABA transaminase.”
GABA is a naturally occurring amino acid that serves as the primary inhibitory neurotransmitter in the central nervous system, which means it reduces the nerve activity. Nerves serve as a link between the brain and the rest of the body. Renquist explained that communication occurs not only from the brain to other tissues but also from tissues back to the brain.
“When the liver produces GABA, it reduces the activity of nerves that connect the liver to the brain. Thus, fatty liver reduces firing activity to the brain by producing GABA” Renquist explained. “The central nervous system detects the decrease in firing and changes outgoing signals that affect glucose homeostasis.”
Caroline Geisler and Susma Ghimire, graduate students in Renquist’s lab, used pharmacological inhibition of liver GABA transaminase in animal models of Type 2 diabetes to see if increased liver GABA synthesis was causing insulin resistance.
“Inhibiting excess liver GABA production restored insulin sensitivity within days,” said Geisler, who is now a postdoctoral researcher at the University of Pennsylvania and the papers’ lead author. “Longer-term GABA-transaminase inhibition resulted in decreased food intake and weight loss.”
Researchers wanted to ensure that their findings would be applicable to humans. Kendra Miller, a research technician in Renquist’s lab, discovered genetic variations near GABA transaminase that were linked to Type 2 diabetes. In collaboration with Washington University researchers, the researchers discovered that in people with insulin resistance, the liver has more highly expressed genes involved in GABA production and release.
The findings form the basis of a clinical trial funded by the Arizona Biomedical Research Commission that is currently underway at Washington University School of Medicine in St. Louis with collaborator Samuel Klein, a co-author on the study and a Washington University professor of medicine and nutritional science. The trial will look into the use of a commercially available, FDA-approved GABA transaminase inhibitor to improve insulin sensitivity in obese people.
“A novel pharmacological target is just the first step in application; we’re years away from anything reaching the local pharmacy,” Renquist said. “Given the gravity of the obesity crisis, these encouraging findings are an important first step that we hope will eventually impact the health of our family, friends, and community.”
