The way to the pancreas is through the liver?
University of Arizona
Today,
Type 2 diabetes is 24 times more prevalent than Type 1. The rise in rates of
obesity and incidence of Type 2 diabetes are related and require new
approaches, according to University of Arizona researchers, who 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," said Benjamin Renquist, an associate professor in the UArizona College of Agriculture and Life Sciences and BIO5 Institute member. "We need another breakthrough."
In
two newly published papers in Cell Reports, Renquist, along with
researchers from Washington University in St. Louis, the University of
Pennsylvania and Northwestern University, outline a new target for Type 2
diabetes treatment.
Renquist,
whose research lab aims to address obesity-related diseases, has spent the last
nine years working to better understand the correlation 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," Renquist
said. "As fat increases in the liver, the incidence of diabetes
increases."
This
suggested that fat in the liver might be causing Type 2 Diabetes, 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, Renquist said.
Renquist
and his collaborators focused on fatty liver, measuring neurotransmitters
released from the liver in animal models of obesity, to better understand how
the liver communicates with the brain to influence metabolic changes seen in
obesity and diabetes.
"We
found that fat in the liver increased the release of the inhibitory
neurotransmitter Gamma-aminobutyric acid, or GABA," Renquist said.
"We then identified the pathway by which GABA synthesis was occurring and
the key enzyme that is responsible for liver GABA production -- GABA
transaminase."
A
naturally occurring amino acid, GABA is the primary inhibitory neurotransmitter
in the central nervous system, meaning it decreases nerve activity.
Nerves
provide a conduit by which the brain and the rest of the body communicate. That
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 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," Renquist said. "That decrease in
firing is sensed by the central nervous system, which changes outgoing signals
that affect glucose homeostasis."
To
determine if increased liver GABA synthesis was causing insulin resistance,
graduate students in Renquist's lab, Caroline Geisler and Susma Ghimire,
pharmacologically inhibited liver GABA transaminase in animal models of Type 2
diabetes.
"Inhibition
of excess liver GABA production restored insulin sensitivity within days,"
said 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."
Researchers
wanted to ensure the findings would translate to humans. Kendra Miller, a
research technician in Renquist's lab, identified variations in the genome near
GABA transaminase that were associated with Type 2 diabetes. Collaborating with
investigators at Washington University, the researchers showed that in people
with insulin resistance, the liver more highly expressed genes involved in GABA
production and release.
The
findings are the foundation of an Arizona Biomedical Research Commission-funded
clinical trial currently underway at Washington University School of Medicine
in St. Louis with collaborator Samuel Klein, co-author on the study and a
Washington University professor of medicine and nutritional science. The trial
will investigate the use of a commercially available Food and Drug
Administration-approved inhibitor of GABA transaminase to improve insulin
sensitivity in people who are obese.
"A
novel pharmacological target is just the first step in application; we are
years away from anything reaching the neighborhood pharmacy," Renquist
said. "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."
