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Old diabetes drug teaches experts new tricks
Date:5/14/2009

Research from the Johns Hopkins Children's Center reveals that the drug most commonly used in type 2 diabetics who don't need insulin works on a much more basic level than once thought, treating persistently elevated blood sugar the hallmark of type 2 diabetes by regulating the genes that control its production.

Reporting in the May 15 issue of Cell, investigators say they have zeroed in on a specific segment of a protein called CBP made by the genetic switches involved in overproduction of glucose by the liver that could present new targets for drug therapy of the disease.

In healthy people, the liver produces glucose during fasting to maintain normal levels of cell energy production. After people eat, the pancreas releases insulin, the hormone responsible for glucose absorption. Once insulin is released, the liver should turn down or turn off its glucose production, but in people with type 2 diabetes, the liver fails to sense insulin and continues to make glucose. The condition, known as insulin resistance, is caused by a glitch in the communication between liver and pancreas.

Metformin, introduced as frontline therapy for uncomplicated type 2 diabetes in the 1950s, up until now was believed to work by making the liver more sensitive to insulin. The Hopkins study shows, however, that metformin bypasses the stumbling block in communication and works directly in the liver cells.

"Rather than an interpreter of insulin-liver communication, metformin takes over as the messenger itself," says senior investigator Fred Wondisford, M.D., who heads the metabolism division at Hopkins Children's. "Metformin actually mimics the action of CBP, the critical signaling protein involved in the communication between the liver and the pancreas that's necessary for maintaining glucose production by the liver and its suppression by insulin."

To test their hypothesis, researchers induced insulin resistance in mice by feeding
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Contact: Ekaterina Pesheva
epeshev1@jhmi.edu
410-516-4996
Johns Hopkins Medical Institutions
Source:Eurekalert

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