This year marks 100 years since the discovery of insulin. It was a scientific breakthrough that made Type 1 diabetes manageable.Type 2 diabetes is now 24 times more common than Type 1. According to University of Arizona researchers who believe that the liver could hold the key to new treatment options, Type 2 diabetes is 24 times more common than Type 1."All the current therapies for Type 2 diabetes aim to lower blood glucose. They are treating a symptom. It is similar to treating flu symptoms by decreasing fever," Benjamin Renquist, associate professor at the UArizona College of Agriculture and Life Sciences and BIO5 Institute member, said. "We need another breakthrough."Renquist and researchers from Washington University, Pennsylvania, Northwestern University have published two papers in Cell Reports that outline a new target in Type 2 diabetes treatment.Renquist's research lab is focused on obesity-related diseases. He has spent nine years trying to understand the relationship between obesity, fatty liver disease, and diabetes. In particular, Renquist has been studying how insulin sensitivity affects liver function.Renquist stated that Type 2 diabetes is caused by obesity. Diabetes incidence increases as fat in the liver increases.Renquist stated that this suggested that Type 2 Diabetes could be caused by excess insulin secretion or resistance in the liver.AdvertisementRenquist and his colleagues focused on fatty liver. They measured neurotransmitters in the liver in animal models that mimic obesity to better understand how the liver interacts with the brain and influence the metabolic changes in obesity and diabetes.Renquist stated that "we found that liver fat increased the release inhibitory neurotransmitter Gamma–aminobutyric acids, or GABA." "We identified the pathway through which GABA synthesis occurred and identified the key enzyme responsible for liver GABA production, GABA transaminase.GABA, a naturally occurring amino acid that decreases nerve activity, is the primary inhibitory neurotransmitter within the central nervous system.The brain and the body communicate through the nerves. Renquist explained that communication goes beyond the brain to other tissues. It also runs back to the brain through tissues.GABA is produced by the liver and decreases the activity of nerves running from the liver to brain. Renquist explained that fatty liver is reducing firing activity to brain by producing GABA. "This decrease in firing is detected by the central nervous, which changes outgoing messages that affect glucose homeostasis.Graduate students from Renquist's laboratory, Caroline Geisler, and Susma Ghimire, tested whether insulin resistance was caused by increased liver GABA synthesis. They also tested whether liver GABA transaminase activity in Type 2 diabetic animal models.AdvertisementGeisler, a postdoctoral researcher at Penn and the lead author of the papers, stated that "inhibition of excess liver GABA manufacturing restored insulin sensitivity within days." "Longer-term inhibition of GABA–transaminase led to decreased food intake and weight gain."Researchers wanted to make sure that the results would be applicable to people. Kendra Miller, a Renquist lab technician, discovered variations in Renquist’s genome that could be linked to Type 2 diabetes. The researchers, who collaborated with Washington University investigators, showed that insulin resistance is associated with higher liver expression of genes involved in GABA production.These findings form the basis of an Arizona Biomedical Research Commission funded clinical trial at Washington University School of Medicine, St. Louis. Samuel Klein, coauthor of the study and a Washington University Professor of Medicine and Nutrition Science, is currently conducting the trial. The trial will examine the commercially available GABA transaminase inhibitor to increase insulin sensitivity in obese patients.Renquist stated that a novel pharmacological target was only the first step of application. It is still years away from any reaching the local pharmacy. These promising findings are an important step in our quest to improve the health of our community, friends, and family due to the severity of the obesity crisis.
