The findings, to be posted by the journal Nature on its Web site on May 18, suggest that drugs designed to block the interaction of the two switch proteins might be effective in treating diabetes, and with few side effects.

Building on their discovery of this master switch in fall 2001, scientists led by Dana-Farbers Bruce Spiegelman, PhD, found that two previously known proteins in mice must dock, one on top of the other, to enable the switch to turn on genes that initiate the livers sugar-making process. Furthermore, when mutations cause a flaw in one of the proteins, the switch no longer can respond to insulin, the hormone that normally regulates sugar manufacture in the liver.

The actual molecular connections between the proteins are potential targets for diabetic therapy, says Spiegelman, the papers senior author. It may be possible to design an oral drug that could block the joining of the two proteins PGC-1alpha and FOXO1 when the switch is stuck in the on position.

The livers manufacture of sugar from raw materials, a process called gluconeogenesis, is designed to provide the body (especially the brain) with necessary glucose when the person has been fasting and isnt obtaining the sugar from food. Glucagon and glucocorticoid hormones initiate the process on by sending signals to liver cells, triggering activity (DNA transcription) in genes that set gluconeogenesis in motion.

Insulin, produced in the pancreas, has the opposite effect, turning off gluconeogenesis when normal feeding resumes. Insulin activates the insulin receptors on liver cells surfaces, which send signals into the cells nuclei where they are received by the switch made up of the PGC-1alpha and FOXO1 proteins.

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Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute
18-May-2003