L. Darryl Quarles

Researchers from the University of Tennessee Health Science Center have discovered a chemical compound that could lower sugar levels as effectively as the diabetes drug Metformin but with a lower dose.

This new approach to diabetes drug discovery has been published in PLOS One, a peer-reviewed open access scientific journal. The research team includes scientists from the University of Tennessee, Knoxville (UTK) and Oak Ridge National Laboratory (ORNL).

Along with his research team, Darryl Quarles, MD, University of Tennessee Medical Group (UTMG) Endowed Professor of Nephrology, director of the Division of Nephrology, and associate dean for Research in the College of Medicine at UTHSC, has been working with a specific protein called GPRC6A, which regulates sugar levels by simultaneously correcting multiple metabolic derangements that underlie Type 2 diabetes function. These derangements include abnormalities in pancreatic β-cell proliferation and insulin secretion, glucose uptake into skeletal muscle, and liver regulation of glucose and fat metabolism.

With over 400 million people suffering from T2D worldwide, the global cost of medicine and prevention is close to a trillion dollars per-year. Frequently associated with obesity and Metabolic Syndrome, T2D is characterized by high blood sugar levels and other metabolic derangements that increases (often doubling) a person’s risk of an early death.

Metformin, a pill that lowers the liver’s production of sugar and decreases risk of mortality, is currently recommended as a first line treatment for T2D. However, there is a need for alternative treatment options when patients are not as responsive to Metformin as their doctors would hope.

Jeremy Smith

Dr. Quarles’ team needed to find a chemical that would activate this protein, so Jerome Baudry, PhD (formerly of UTK but now at the University of Alabama in Huntsville) and Jeremy Smith, PhD, Governor’s Chair at UTK and director of the Center for Molecular Biophysics at ORNL, employed sophisticated computer simulations using high-performance computing to screen potential chemicals that would trigger the desired activation.

The computations at UTK/ORNL found several chemicals that might activate the protein, and each were tested by the Quarles laboratory at UTHSC. A team of medicinal chemists at UTHSC used the results to synthesize related molecules for pre-clinical testing, and one of them, in particular, was highly potent in stimulating insulin secretion and lowering sugar levels in mice.

“Using a computational, structure-based high-throughput screening approach, we identified novel compounds predicted to bind to domains of GPRC6A,” said Dr. Quarles. “Experimental testing, additional chemical modifications and functional analysis identified a compound, synthesized by Duane Miller, PhD, professor emeritus in the Department of Pharmaceutical Sciences in the College of Pharmacy at UTHSC, called DJ-V-159 to be the most potent in stimulating insulin secretion in β-cells and lowering serum glucose in wild-type mice.”

“This chemical compound lowers sugar levels in mice as effectively as Metformin but with a 30 times lower dose. It therefore is a good starting point for the development of a new and effective drug to fight diabetes,” said Dr. Smith.

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