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, according to University of Arizona researchers, who believe the liver may be key to innovating new treatments.
“All current therapeutics for type 2 diabetes are primarily aimed at lowering blood sugar. So you’re treating a symptom, similar to the flu, by lowering the fever, ”said Benjamin Renquist, Associate Professor at the 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, particularly 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,” said 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 said .
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 increased the release of the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA,” said Renquist. “We then identified the route by which GABA synthesis takes place and the key enzyme responsible for GABA production in the liver – 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, Renquist explained.
“When the liver produces GABA, it decreases the activity of the nerves that run from the liver to the brain. Thus, by producing GABA, the fatty liver decreases the brain’s fire activity,” said 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.
“Inhibiting excessive GABA production by the liver restored insulin sensitivity in days,” said Geisler, now a postdoctoral fellow at the University of Pennsylvania and lead author of the papers. “Prolonged inhibition of GABA transaminase resulted in 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 from Washington University, the researchers showed that in people with insulin resistance, the liver expresses more genes that are involved in the production and release of GABA.
The results form the basis of a clinical study funded by the Arizona Biomedical Research Commission that is currently being conducted at the Washington University School of Medicine in St. Louis with collaborator Samuel Klein, study co-author and Professor of Medicine and Nutrition at Washington University, running. The study will investigate the use of a commercially available Food and Drug Administration-approved GABA transaminase inhibitor to improve insulin sensitivity in obese people.
“A novel pharmacological target is only the first step in its application; we’re years away from anything getting to the neighborhood pharmacy, ”said 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.”
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