Chris Newgard, Ph.D., outlined his work with diabetes. (photo by Dana Johnson)
Symposium speakers highlight diabetes research advances
The latest advances in diabetes research took center stage at a symposium this week in celebration of the Vanderbilt Diabetes Center. The symposium speakers represented “a veritable who’s-who among diabetes research leaders,” said Dr. Steven G. Gabbe, dean of the Vanderbilt University School of Medicine as he welcomed the speakers and presented them with Vanderbilt medals.
Each speaker, in turn, praised the efforts of the Vanderbilt Diabetes Center, which is celebrating more than a quarter century of discovery, training, and patient care. “This is truly one of the meccas of diabetes research,” said Christopher B. Newgard, Ph.D., Gifford O. Touchstone Jr. and Randolph Touchstone Distinguished Chair in Diabetes Research at the University of Texas Southwestern Medical Center.
Dr. C. Ronald Kahn, president and director of the Joslin Diabetes Center and Mary K. Iacocca Professor at Harvard University, kicked off the symposium with a presentation focused on the molecular underpinnings of insulin resistance—the earliest detectable defect in individuals with Type II diabetes. When tissues become resistant to the action of insulin, they are no longer able to effectively use sugar, leading to high blood sugar levels.
Kahn’s laboratory has used genetically modified mice and cells to search for the molecular defects that impair the ability of cells to respond to insulin. By modifying multiple genes in mice, Kahn and colleagues have reproduced the effects of the human disease—providing useful models for further studies.
In collaboration with Dr. Mark A. Magnuson, assistant vice chancellor for Research at Vanderbilt, Kahn also has engineered mice with deletions of the insulin receptor only in specific tissues. These studies have defined roles for insulin in tissues where insulin action was controversial, like the brain and the beta cells of the pancreas. “These mouse models are providing a new way of thinking about and exploring the genetics of diabetes,” Kahn said.
Newgard described his research as having “two hopelessly ambitious goals”—engineering cell lines to treat Type I diabetes and developing new therapeutic strategies for Type II diabetes.
The notion of transplanting insulin-producing cells to replace destroyed pancreatic cells in Type I diabetics has been a long-term goal of the entire diabetes research field. A necessary prelude to providing such cells, Newgard said, is to fully understand “the plumbing of the beta cell”—how this specialized pancreatic cell senses blood sugar and responds by secreting insulin. Newgard’s group is working to pinpoint the genes that participate in this response.
Newgard also presented the results of new studies aimed at understanding how over-storage of fat in cells contributes to diabetes. The studies utilize what he calls “fatso rats,” rats that develop all of the symptoms of diabetes after eating a high-fat diet for only six to 10 weeks. “Our goal is to find ways to reverse this diabetes syndrome,” Newgard said. He and colleagues are introducing genes into the rats that activate fat burning to try to correct the fat-induced diabetic state.
Dr. Luciano Rossetti, professor of Medicine and co-director of the Albert Einstein College of Medicine Diabetes Research and Training Center, focused on the balance of forces that regulate weight gain or loss. Because obesity is intricately linked to the “epidemic” of Type II diabetes, it is critical to define the pathways that respond to nutrient intake and usage, Rossetti said.
Rossetti and colleagues have concentrated on the role of a brain structure called the hypothalamus in sensing nutrient intake and controlling metabolism and feeding behavior. “Anything that blocks the regulatory responses of the hypothalamus can break the balance and tip the scale toward insulin resistance,” Rossetti said.
Dr. Gerald I. Shulman, professor of Medicine and Cellular and Molecular Physiology at Yale University, concluded the symposium with a presentation describing his group’s search for the biochemical defects that underlie insulin resistance in Type II diabetes.
Shulman, who spent time as a student in the Vanderbilt Diabetes Center summer research program, is responsible for applying the approach of NMR spectroscopy to human investigation. NMR spectroscopy can be used to “open a window into the biochemistry of the living cell in people,” Shulman said, providing the opportunity to non-invasively study biochemical pathways.
Shulman and colleagues have used this technique to define biochemical defects associated with insulin resistance. They discovered that transport of blood sugar into muscle cells is impaired in patients with Type II diabetes. Efforts to understand why muscle cells cannot effectively take in sugar in response to insulin led Shulman to examine fatty acid levels and metabolism. “The best predictor for insulin resistance in patients is free fatty acid levels,” Shulman said.
But fat is not all bad, he noted. “It’s not so much how much fat we have as where it’s distributed within the tissue beds. Too much fat in muscle and liver cells sets up those tissues for insulin resistance.” Using mouse models, Shulman’s group has defined a molecular target for new drugs that could block fat-induced insulin resistance.