A team of researchers in the University of Tennessee Health Science Center’s College of Medicine has been awarded a $1.98 million grant from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), a division of the National Institutes of Health, for a novel approach to studying diabetes.
Darryl Quarles, MD, University of Tennessee Medical Group Endowed Professor of Nephrology, director of the Division of Nephrology, and associate dean for Research in the College of Medicine, and Lu Lu, MD, professor of Genetics, Genomics and Informatics, are the dual principal investigators on the study that focuses on a specific protein related to metabolic function that could be a key in developing new drugs to treat diabetes.
The project, titled “Genetic and Environmental Determinants of GPRC6A Regulation of Energy Metabolism Using Genetically Engineered Mice and Systems Biology,” focuses on the role of a specific protein called GPRC6A. It is a G-protein coupled receptor notable for its nutrient-sensing abilities and regulation of energy metabolism. In experiments using mouse models, the research team has found that if they delete GPRC6A, a cascade of adverse consequences occur, including obesity, fatty liver, and glucose intolerance. Conversely, if they activate the protein, it prevents high-fat-diet-induced metabolic complications in the liver, and releases hormones that coordinate metabolic functions between the liver and other organs.
“We’ve found that this receptor directly regulates glucose and fat metabolism in the liver and muscle through pathways that do not involve traditional factors, such as insulin,” Dr. Quarles said. “In addition, GPRC6A coordinates the release of an ensemble of metabolically active hormones, such as insulin, FGF21, testosterone, GLP1 and IL-6. Its ligands and multiple effects on glucose and fat metabolism creates a new schema for understanding energy metabolism. It’s unique.”
In explaining the significance and promise GPRC6A holds in unraveling the complexities of diabetes, Dr. Lu noted that current studies of the disease and metabolic disorders focus on the pancreas and pancreas-isolated hormones. “But this G-protein receptor is unique in what it does in many organs,” he said. “Our project focuses on the liver, but we can extend this research to the brain, to the bone, to other organs.”
Using molecular and cell biology and mouse genitive approaches, and system genetics headed by Dr. Lu, the team intends to investigate GPRC6A’s function in the liver as a prototype for understanding how it controls glucose and fat metabolism in other organs. Their aim is to indentify the gene networks that GPRC6A regulates in energy equilibrium, and determine the genetic modifiers that influence its effects. They will also work to validate it as a target for developing new drugs to treat Type 2 diabetes and metabolic syndrome.