Protein Holds Promise As New Diabetes Drug Target

When Dr. Mark A. Magnuson arrived at Vanderbilt in 1985 as a postdoctoral fellow, he took on a challenging project – cloning the gene for the enzyme glucokinase. At the time, it was known that glucokinase was important for the metabolism of glucose, the sugar that climbs dangerously high in the blood of patients with diabetes. The cloning project was a success, and now, with the work by Hoffman-La Roche, glucokinase is taking center stage as a new drug target for type 2 diabetes.

"There have not been that many new drugs for the treatment of diabetes ever discovered, and this one is unique in its mechanism of action," said Magnuson, assistant vice chancellor for Research and a co-author of the report. "By turning on glucokinase, this novel compound improves insulin secretion by the pancreas and stimulates glucose usage by the liver, both of which are abnormal in diabetes." Magnuson cautions that it's too early to tell what the real value of a glucokinase-activating drug might be. Clinical trials are still in the planning stage. "It has dramatic effects in animals, suggesting it has the potential to be a very powerful new drug," he said.

The promise of such a drug comes from its target, glucokinase. This enzyme – a "glucose sensor" – plays a key role in maintaining sugar balance in the body. It acts mainly in the pancreatic beta cell, where it is important for insulin secretion, and in the liver, where it participates in how glucose is used and stored. Because both insulin secretion and glucose utilization by the liver are defective in patients with diabetes, a single drug that improves both functions is an attractive possibility, Magnuson said.

In the years since they cloned the glucokinase gene, Magnuson and Dr. Daryl K. Granner, director of the Vanderbilt Diabetes Center – joined by several other Vanderbilt laboratories along the way – have ferreted out nuances of how the enzyme works. Most recently, Magnuson and colleagues have genetically engineered mice that lack glucokinase only in selected tissues, like the beta cell or liver, to understand tissue-specific roles and regulation.

"Studies performed at Vanderbilt were essential for demonstrating the importance of this enzyme," Magnuson said.

After the glucokinase gene was cloned, other investigators identified mutations in the human gene. Mutations that cause the enzyme not to function properly have been linked to a form of diabetes called maturity-onset diabetes of the young type 2 (MODY2). And mutations that activate glucokinase – much like the newly discovered compound – cause persistent hyperinsulinemic hypoglycemia of infancy, a condition characterized by high insulin and low blood glucose. These observations solidified the view that glucokinase would be an ideal target for an antidiabetic drug, Magnuson said.

Even so, he added, "no one ever thought we would find a drug that directly targets the enzyme and activates it." The investigators at Hoffman-La Roche were actually screening for compounds that would work in an indirect way to alter glucokinase activity when they found the chemical described in the Science report.

"It was a serendipitous discovery," Magnuson said. "One compound in one of their chemical libraries (of over 120,000 compounds) happened to bind to and activate glucokinase." Other companies that have also been searching for compounds to affect glucokinase activity have not been so fortunate, he said.

The Hoffman-La Roche team demonstrated that the new compound enhances insulin release from isolated rat pancreatic islets. It also lowers blood glucose levels and improves results of oral glucose tolerance tests in rats and mice with diabetes.

Though it will be several more years before clinical trials begin to reveal whether or not drugs based on this compound are effective therapies for diabetes, Magnuson marvels at the progress that's been made since the glucokinase cloning project first got started.

"It really emphasizes the value of basic science research, and how studying enzymes and the mechanisms for regulation of blood glucose can yield important clues and unpredicted things that pay out over time," he said. "Now we're beginning to see the promise of some very basic science research that was done here at Vanderbilt."