Researchers have discovered a factor that controls blood sugar's manufacture in a novel way: by limiting the supply of its building blocks. The findings are reported in the April issue of the journal Cell Metabolism, published by Cell Press.

The study found that mice deficient for KLF15, a member of the so-called Krppel-like family of transcription factors, become severely lacking in the blood sugar glucosea primary energy source for the body and the sole source for the brainafter a period of overnight fasting. The researchers traced that deficiency back to an inability to produce new glucose in the liver, a process known as gluconeogenesis, due to a defect in the processing of amino acids. Amino acids are the main ingredients of proteins and the source of a key substrate in blood sugar's production.

"Gluconeogenesis is a complicated process," said Mukesh K. Jain of Case Western Reserve University. "It fundamentally requires two big things: the building blocks and the [glucose-building] enzymes that make it all happen. A lot of previous work has focused on the enzymes."

"We've found the first defect [in glucose production] due to a loss of substrate," added Susan Gray of Brigham and Women's Hospital.

During fasting, the supply of glucose derived from food dries up, Gray explained. In response, the body first breaks down liver glycogen, the principal storage form of glucose. However, the body "goes through those stores overnight," she said.

Once the reserves are depleted, the body must rely on the synthesis of new glucose, primarily in the liver, to prevent a life-threatening shortage, a condition known as hypoglycemia. The de novo synthesis of glucose depends on the availability of a substrate molecule that comes from an amino acid.

The researchers found that mice with a targeted deletion of KLF15 display severe hypoglycemia after an overnight fast. They further found evidence that defective amino acid b
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Contact: Erin Doonan
edoonan@cell.com
617-397-2802
Cell Press
3-Apr-2007