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Finding of key blood sugar controller could yield new diabetes drugs

on, the scientists believe future drugs might be designed to block this protein known as a "transcription co-activator" in order to turn down glucose production in diabetics. The study findings "suggest a new target [for drugs] in diabetes," says Spiegelman, noting that in some patients, excess blood sugar is difficult to control with current treatments.

Spiegelmans team, which works on both cancer and diabetes, has studied fat cells and the metabolic processes that produce energy from food. He notes that the bodys mechanism for maintaining a certain blood sugar level "is exquisitely sensitive" and fine-tunes blood sugar "whether youre eating around the clock or are starving." Gluconeogenesis in the liver is controlled by hormones produced in the pancreas, including glucagon and insulin.

Normally, the liver turns itself on and off to maintain blood sugar balance, "but in diabetes, the liver is just pumping glucose all the time because its stuck in the on position," say Spiegelman, who is also a professor of cell biology at Harvard Medical School. For some 20 years, he said, scientists have searched for but failed to discover the molecular switch that triggers the process of gluconeogenesis.

Spiegelmans lab had previously studied PGC-1, a protein that regulations gene transcription, or activity, in brown fat and in muscle. In 1998, they showed that PGC-1 became more active in muscles and fat of mice exposed to cold. To test whether it had a role in gluconeogenesis, the scientists loaded harmless viruses with PGC-1 genes and infected mice with them. The PGC-1 turned on other genes that triggered glucose production, and the mice became "hyperglycemic" an excess of sugar in the blood.

"That was a real eureka moment," says Spiegelman. In other test with mice bioengineered by Kahn at the Joslin Diabetes Center to lack insulin activity, the scientists found that the absence of insulin spurred a rise in PGC-1, as they would ex
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Contact: Janet Haley Dubow
janet_haley@dfci.harvard.edu
617-632-4090
Dana-Farber Cancer Institute
12-Sep-2001


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