April 4, 2003

‘Metabolomics’ introduced as possible diabetes research tool

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Christopher B. Newgard, Ph.D. outlines his novel research with diabetes at last week’s lecture. (photo by Dana Johnson)

‘Metabolomics’ introduced as possible diabetes research tool

Twelve years ago, Christopher B. Newgard thought he and his colleagues had discovered a way to create insulin-producing cells that could be transplanted as a potential treatment — or even a cure — for diabetes.

His optimism was premature. Newgard and his group at the University of Texas Southwestern Medical Center in Dallas created a rat cell line that would secrete insulin in response to glucose, but they were never able to achieve the same thing with human cells.

So began for Newgard, who has since moved his laboratory to Duke University Medical Center, a period of “retrenchment” — spending the time needed to understand better how the marvelous insulin-producing beta cell works, and how a host of body tissues, hormones, enzymes and other factors work together to regulate glucose metabolism.

What he and his colleagues have discovered is nothing short of astonishing, and it could open the door to new treatments for diabetes. Newgard shared some of these discoveries with Vanderbilt researchers last week as part of the Albert & Miriam Weinstein Lectureship, named for a former clinical professor of medicine at Vanderbilt and his wife who were strong supporters of diabetes research.

Newgard, who has a Ph.D. in biochemistry, is director of the Sarah W. Stedman Nutrition and Metabolism Center at Duke. He is nationally known for his research, which employs a variety of approaches, from genetic engineering to mass spectroscopy, to improve understanding of diabetes at the molecular level.

“Chris is an unusual thinker,” said Dr. Daryl K. Granner, director of the Vanderbilt Diabetes Center. “He’s very creative in devising tools to manipulate cells. He was one of the earliest people to use adenovirus as vectors to carry genes in and alter cellular metabolism.”

Newgard and his colleagues have used adenovirus vectors to help identify the steps by which glucose stimulates insulin secretion in rat beta cell lines, and how accumulation of fat in the cell can interfere with this process. Lipid “over-storage” is thought to contribute to abnormal beta cell functioning, one of the hallmarks of type 2 diabetes.

The researchers also have created cell lines that are resistant to attack by cytokines, part of the body’s immune defenses. A misdirected immune attack that destroys the pancreatic beta cells is responsible for type 1 diabetes.

These two lines of inquiry could aid in the development of transplantable cell lines that behave like normal beta cells and which are protected against immune attack.

Another area of research in the Newgard laboratory involves a model of type 2 diabetes in rats fed a high-fat diet. These animals develop many of the “signature features” of type 2 diabetes in humans, including high levels of glucose and fat in the bloodstream. Circulating levels of insulin are also high, indicating that the animals are “resistant” to the hormone, which normally facilitates glucose transport into muscle tissue.

In an experiment reported three years ago, the researchers infused the rats with an adenovirus that carried the gene for leptin, a hormone produced by fat tissue that is involved in the regulation of appetite, energy expenditure and body weight. Within five days, circulating levels of glucose and insulin were back to normal, and insulin sensitivity of muscle tissue was restored. Leptin has been tested in humans as a potential treatment for obesity, but results to date have been disappointing.

More recently, Newgard has collaborated with Masakazu Shiota, D.V.M., Ph.D., assistant professor of Molecular Physiology and Biophysics at Vanderbilt, on studies of malonyl-CoA decarboxylase, an enzyme that essentially can “melt fat” out of tissue.

Newgard and his colleagues figured out a way to “over-express” the gene for the enzyme, via the adenovirus vector, in the rats’ liver, where it selectively melted fat out of liver cells.

Meanwhile, Shiota miniaturized a technique for measuring glucose flux and insulin sensitivity in larger animals so it could be applied to studies of rats and mice. The technique enabled the researchers to measure how much radiolabeled glucose was absorbed by muscle in response to a continuous infusion of insulin.

The researchers found that when the enzyme was over-expressed and specifically melted fat out of the liver, insulin sensitivity in the muscles improved. “I remain astonished by these results,” Newgard said. “Somehow melting the fat out of the liver is a signal to restore insulin action in the muscle. So there’s tissue networking going on (messages sent between organs and tissues) that we are only at the threshold of understanding.”

To determine what’s going on, Newgard and his colleagues are using mass spectroscopy, a technique for separating molecules by their mass, to identify the products of liver and fat metabolism that may influence insulin sensitivity in muscle.

“We have genomics. We have proteomics. This is the dawn of ‘metabolomics,’ “ Newgard said. “Just like we look at all the differentially expressed genes or all of the proteins, we can be looking at the products of the enzymes, which are the metabolites … (and) see what it is that … may be linked to insulin resistance.”

Newgard praised Vanderbilt’s diabetes center as one of the best in the world. “The critical mass here is really astonishing,” he said, “ … just lab after lab of people who are nationally and internationally recognized.”

Still another of Newgard’s research projects involves proteins that are involved in glucose production and disposal in the liver. Some of these proteins, called glycogen-targeting subunits, facilitate the storage of glucose in the liver in the form of glycogen.

Newgard and his colleagues have made a new subunit that, when over-expressed in the liver, increases glycogen formation, lowers blood glucose levels to normal and even reduces food intake in diabetic rats.

Despite these advances in understanding, Newgard said he was not sure when, or if, safe and effective treatments would be developed to reverse obesity and diabetes.

Still, “it’s an exciting time to be involved,” he added. “Are we making progress in understanding molecular pathways, identifying new players that contribute to all of this, (and) deploying sophisticated new technologies? Yes, definitely.”