Share that
items
You are free to share this article under the Attribution 4.0 International license.
Researchers believe the liver could be the key to new preventive treatments for type 2 diabetes.
This year marks the 100th anniversary of the discovery of insulin, a scientific breakthrough that transformed type 1 diabetes, once known as juvenile diabetes or insulin-dependent diabetes, from an incurable disease to a treatable condition.
Today type 2 diabetes is 24 times more common than type 1 diabetes. The rise in obesity and the incidence of type 2 diabetes are related and require new approaches, the researchers say.
“All current therapeutics for type 2 diabetes are primarily aimed at lowering blood sugar. So they’re treating a symptom, similar to the flu, by lowering the fever, ”says Benjamin Renquist, associate professor at the University of Arizona College of Agriculture and Life Sciences and a member of the BIO5 Institute. “We need another breakthrough.”
In two newly published articles in Cell Reports, Renquist, along with researchers from Washington University in St. Louis, the University of Pennsylvania, and Northwestern University, outlines a new goal for the treatment of type 2 diabetes.
Renquist, whose research lab aims to study obesity diseases, has worked for the past nine years to better understand the relationship between obesity, fatty liver, and diabetes, specifically how the liver affects insulin sensitivity.
“Obesity is known to be a cause of type 2 diabetes, and we have long known that the amount of fat in the liver increases with obesity,” says Renquist. “As the fat in the liver increases, the incidence of diabetes increases.”
This suggested that fat in the liver could cause type 2 diabetes, but how fat in the liver can make the body resistant to insulin or cause the pancreas to produce excessive insulin remains a mystery, Renquist says .
Renquist and co-workers focused on fatty liver and measured the neurotransmitters released by the liver in animal models of obesity to better understand how the liver communicates with the brain to affect metabolic changes in obesity and diabetes.
“We found that fat in the liver increases the release of the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA,” says Renquist. “We then identified the route by which GABA synthesis took place and the key enzyme responsible for liver GABA production – GABA transaminase.”
GABA, a naturally occurring amino acid, is the primary inhibitory neurotransmitter in the central nervous system, meaning that it decreases nerve activity.
Nerves provide a conduit through which the brain and the rest of the body communicate. This communication is not only from the brain to other tissues, but also from tissues back to the brain, explains Renquist.
“When the liver produces GABA, it reduces the activity of the nerves that run from the liver to the brain. Thus, by producing GABA, the fatty liver reduces the fire activity of the brain, ”says Renquist. “This decrease in firing is sensed by the central nervous system, which changes outgoing signals that affect glucose homeostasis.”
To determine whether increased GABA synthesis in the liver causes insulin resistance, the PhD students in Renquist’s laboratory, Caroline Geisler and Susma Ghimire, pharmacologically inhibited liver GABA transaminase in animal models of type 2 diabetes.
“The inhibition of excessive GABA production by the liver restored insulin sensitivity within days,” says Geisler, now a postdoctoral fellow at the University of Pennsylvania and lead author of the papers. “Prolonged inhibition of GABA transaminase led to decreased food intake and weight loss.”
The researchers wanted to make sure that the results would be transferred to humans. Kendra Miller, a research technician at Renquist’s lab, identified variations in the genome near GABA transaminase that have been linked to type 2 diabetes. Working with researchers at Washington University, the researchers showed that in people with insulin resistance, the liver expresses more genes involved in GABA production and release.
The results form the basis of a clinical study funded by the Arizona Biomedical Research Commission that is currently ongoing at the Washington University School of Medicine in St. Louis with collaborator Samuel Klein, study co-author and professor of medicine and nutritional science. The study will investigate the use of a commercially available Food and Drug Administration-approved GABA transaminase inhibitor to improve insulin sensitivity in people with obesity.
“A novel pharmacological target is only the first step towards application; We are years away from anything reaching the local pharmacy, ”says Renquist. “The scale of the obesity crisis makes these promising results an important first step that we hope will ultimately have an impact on the health of our family, friends and community.”
Source: University of Arizona
