Issue 159 Item 14 New Target for Antidiabetic Agents Identified

U.S. researchers identify a protein that could serve as a new target for drugs designed to treat type II diabetes.

The protein, known as TRB3, is actually a homolog of a protein found in the fruit fly Drosophila tribbles, senior author Dr. Marc Montminy, from the Salk Institute for Biological Studies in La Jolla, California, and colleagues note.

The focus on TRB3 was the result of a search to identify proteins that modulate the activity of Akt, a main target of insulin that blocks hepatic glucose output when glucose is available from food. Mice lacking the Akt gene demonstrate insulin resistance similar to that seen in humans with type II diabetes.

Dr. Montminy’s team found that TRB3 acts as a negative modulator of Akt and that its expression is increased under fasting conditions. By binding to Akt, TRB3 prevents the enzyme from being activated by insulin, leading to increased glucose output from the liver.

Elevated hepatic levels of TRB3 RNA and protein were identified in diabetic mice compared with wild-type mice, the authors report. Hepatic overexpression of TRB3 was associated with hyperglycemia and glucose intolerance.

Based on these findings, the researchers suggest that TRB3 may be an "attractive drug target in the treatment of type II diabetes." Science 2003;300:1574-1577.

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