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Mouse with designer liver has enhanced glucose tolerance and improved insulin response

(La Jolla, CA). A collaborative effort led by The Burnham Institute's Gen-Sheng Feng has created a mouse with improved glucose tolerance and insulin activity in the liver, and generated new findings about insulin-signaling in the liver that could prove useful in understanding the pathogenesis of type 2 diabetes. These results, to be published by Nature Medicine in May, were made available to the scientific community by advance posting online at the journal's website on April 10th.

The liver plays a major role in the uptake of glucose from the bloodstream, its storage, and regulation. Insulin resistance in the liver is a crucial factor in the development of hyperglycemia and hypertriglyceridemia in individuals who suffer type 2-diabetes. Precisely how insulin-initiated signals are modulated in liver cells for glucose uptake and metabolism is unknown.

Gen-Sheng Feng, Ph.D., a Professor in The Burnham Institute's Signal Transduction Program, has focused his efforts on a recently discovered protein called Gab1. Gab1 has a structure that is similar to other proteins in a family known as Insulin Receptor-Signaling, or IRS, proteins. IRS proteins relay signals initiated by insulin receptors and thus play a critical role in insulin regulation inside cells. Biochemical studies on Gab1 in cell cultures suggested that Gab1 is also involved in insulin signaling, but it is not clear how Gab1 acts to control insulin activity in the liver.

To learn how Gab1 functions in the liver, Feng used a highly advanced genetic engineering technology, called tissue-specific gene deletion, to create a mouse in which the Gab1 gene was deleted, or "knocked out", from the liver, and only the liver. Offsprings were termed "LGKO" for liver-Gab1 knockout mice.

Dr. Feng's laboratory, in collaboration with Drs. Andrea Hevener and Jerrold Olefsky at the University of California, San Diego, conducted a thorough investigation of the glucose metabolism and insulin
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Contact: Nancy Beddingfield
nbeddingfield@burnham.org
858-646-3146
Burnham Institute
12-Apr-2005


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