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Diabetes clue may improve treatment

BY: LEIGH MACMILLAN

9/28/2001 - A team of prominent diabetes research laboratories has identified a key part of the liver’s sugar production machinery. Because over-production of sugar is a problem in diabetes, the finding could lead to better treatments for the disease, said Dr. Daryl K. Granner, Joe C. Davis Professor of Biomedical Science and director of the Vanderbilt Diabetes Center and one of the authors of the paper published recently in Nature.

Blood sugar is the major energy source for mammalian cells, with certain cell types like brain cells and red blood cells being nearly completely dependent on it. The ability of the liver to manufacture sugar ensures steady supplies and is especially important during periods of fasting—even short ones––and starvation.

It has been known for some time that an array of hormones controls liver sugar production by turning on genes for components of the production machinery. But the factors required for turning on these genes have remained elusive until now. Granner’s group, along with investigators at the Dana-Farber Cancer Institute and Joslin Diabetes Center at Harvard and at the University of Texas Southwestern, has demonstrated that a protein called PGC-1 is key to the liver’s manufacture of glucose (sugar), a process called gluconeogenesis.

The investigators discovered that PGC-1 is present in the livers of fasting mice and in the livers of three different mouse models of increased gluconeogenesis. They showed that in cultured cells PGC-1 increases glucose production and participates in turning on genes involved in gluconeogenesis.

“PGC-1 induces the expression of an entire set of gluconeogenic genes,” Granner said. Especially important in this set is the gene for the protein PEPCK, an enzyme that acts as the gatekeeper for sugar production. The PEPCK gene is near and dear to Granner—his group has focused for many years on how hormones turn the gene on and off and how hormonal control of PEPCK relates to gluconeogenesis.

“It takes a huge complex of protein factors to regulate the PEPCK gene,” Granner said. In the current study, John Stafford, an M.D./Ph.D. student in Granner’s laboratory, was able to demonstrate how PGC-1 fit into the complex. “Work over the last 15 years in identifying all of these various protein factors allowed us to very quickly identify where PGC-1 is working to regulate gluconeogenesis.”

Knowing exactly where and how PGC-1 works could be important to developing drugs that suppress the liver’s sugar production—an attractive therapeutic target in diabetes, Granner said. In patients with poorly controlled diabetes, excess glucose production by the liver contributes to excessive blood sugar levels during fasting and after meals.

Metformin, a drug commonly used to treat diabetes, is thought to work by reducing liver glucose production, but how it does this is unknown. “Defining and characterizing the molecules that control gluconeogenesis is obviously central to understanding one of the major problems in diabetes and might allow the design of more focused drugs,” Granner said.

Granner credited the collaboration between four laboratories with making rapid progress on the question of liver sugar production. “What would’ve taken one laboratory years to do, if it could’ve been done at all, was done in a few months,” he said.

Stafford, now in his third year of medical school at Vanderbilt, worked closely with M.D./Ph.D. student J. Cliff Yoon in Bruce M. Spiegelman’s laboratory at Harvard Medical School. The two other collaborating groups are headed by C. Ronald Kahn and Christopher B. Newgard. The research was supported by the National Institutes of Health.

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