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J. Biol. Chem., Vol. 277, Issue 46, 43565-43571, November 15, 2002

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Regulation of Insulin Receptor Function by a Small Molecule Insulin Receptor Activator^*

Celia Pender, Ira D. Goldfine, Vara Prasad Manchem^§, Joseph L. Evans^§, Wayne R. Spevak^§, Songyuan Shi^§, Sandhya Rao^§, Sonia Bajjalieh^§, Betty A. Maddux, and Jack F. Youngren^¶

From the  Mount Zion Medical Center, University of California, San Francisco, California 94143-1616 and ^§ Telik, Incorporated, South San Francisco, California 94080

In type 2 diabetes mellitus, impaired insulin signaling leads to hyperglycemia and other metabolic abnormalities. TLK19780, a non-peptide small molecule, is a new member of a novel class of anti-diabetic agents that function as activators of the insulin receptor (IR) -subunit tyrosine kinase. In HTC-IR cells, 20 µM TLK19780 enhanced maximal insulin-stimulated IR autophosphorylation 2-fold and increased insulin sensitivity 2-3-fold. In contrast, TLK19780 did not potentiate the action of insulin-like growth factor-1, indicating the selectivity of TLK19780 toward the IR. The predominant effect of TLK19780 was to increase the number of IR that underwent autophosphorylation. Kinetic studies indicated that TLK19780 acted very rapidly, with a maximal effect observed 2 min after addition to insulin-stimulated cells. In 3T3-L1 adipocytes, 5 µM TLK19780 enhanced insulin-stimulated glucose transport, increasing both the sensitivity and maximal responsiveness to insulin. These studies indicate that at low micromolar levels small IR activator molecules can enhance insulin action in various cultured cells and suggest that this effect is mediated by increasing the number of IR that are tyrosine-phosphorylated in response to insulin. These studies suggest that these types of molecules could be developed to treat type 2 diabetes and other clinical conditions associated with insulin resistance.

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