Finding of key blood sugar controller could yield new diabetes drugs

September 12, 2001

BOSTON--Dana-Farber Cancer Institute researchers have discovered the long-sought molecular "switch" that regulates the liver's production of glucose, the sugar that fuels the brain but which builds up dangerously in the bloodstream of diabetics because this switch doesn't turn off. The researchers say it may be possible to design new drug treatments for diabetes as a result of the work.

The finding describes for the first time the exact on-off mechanism that in normal people helps the body maintain a precise level of glucose in the blood. It's a delicate and crucial balance. The brain depends on a constant supply of glucose no matter whether the person is eating a big meal or fasting. But the healthy range of blood sugar is narrow, and when there's too much, as in diabetes, the person is prone to serious complications.

J. Cliff Yoon, MD, MPH, and others in the laboratory of Bruce Spiegelman, Ph.D., in the department of cancer biology at DFCI are publishing the finding in the Sept. 13 issue of Nature. Other authors include Christopher B. Newgard, Ph.D., at the University of Texas Southwest Medical Center, and C. Ronald Kahn, MD, president and director of the Joslin Diabetes Center and professor of medicine at Harvard Medical School.

The biochemical switch is a previously known protein called PGC-1 that is active in liver cells, where glucose is made and secreted into the blood stream for transport to the body's organs. The manufacture of glucose, known as gluconeogenesis, normally is turned on when a person who has fasted for a number of hours, resulting in less glucose in the blood. Insulin, the hormone that helps the body use glucose properly, signals the liver to turn off glucogenesis when there is danger of high blood sugar. But insulin is lacking or ineffective in the roughly 16 million people in the United States who have diabetes.

Now that they've shown PGC-1 is the key regulator that insulin and other hormones act 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.

Spiegelman's 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 body's mechanism for maintaining a certain blood sugar level "is exquisitely sensitive" and fine-tunes blood sugar "whether you're 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 it's 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.

Spiegelman's 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 expect if insulin normally acts on PGC-1 to turn down gluconeogenesis.
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Other current or former members of the Spiegelman lab involved in the research include Pere Puigserver, MD, Ph.D.; James Rhee, Ph.D.; Jerry Donovan and Zhidan Wu.

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

Dana-Farber Cancer Institute (www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.

Note: Spiegelman et al have another paper in the same issue of Nature: "CREB regulates hepatic gluconeogenesis via the co-activator PGC-1." For additional information, contact: Suzanne Clancy, 858-453-4100 Ext. 1340

Dana-Farber Cancer Institute

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