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A Novel Small Molecule That Directly Sensitizes the Insulin Receptor In Vitro and In Vivo

¹ Telik, Inc., South San Francisco, California
² Mount Zion Medical Center, University of California at San Francisco, San Francisco, California
³ Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, New York.

Insulin resistance, an important feature of type 2 diabetes, is manifested as attenuated insulin receptor (IR) signaling in response to insulin binding. A drug that promotes the initiation of IR signaling by enhancing IR autophosphorylation should, therefore, be useful for treating type 2 diabetes. This report describes the effect of a small molecule IR sensitizer, TLK16998, on IR signaling. This compound activated the tyrosine kinase domain of the IR ß-subunit at concentrations of 1 µmol/l or less but had no effect on insulin binding to the IR -subunit even at much higher concentrations. TLK16998 alone had no effect on IR signaling in mouse 3T3-L1 adipocytes but, at concentrations as low as 3.2 µmol/l, enhanced the effects of insulin on the phosphorylation of the IR ß-subunit and IR substrate 1, and on the amount of phosphatidylinositol 3-kinase that coimmunoprecipitated with IRS-1. Phosphopeptide mapping revealed that the effect of TLK16998 on the IR was associated with increased tyrosine phosphorylation of the activation loop of the ß-subunit tyrosine kinase domain. TLK16998 also increased the potency of insulin in stimulating 2-deoxy-D-glucose uptake in 3T3-L1 adipocytes, with a detectable effect at 8 µmol/l and a 10-fold increase at 40 µmol/l. In contrast, only small effects were observed on IGF-1–stimulated 2-deoxy-D-glucose uptake. In diabetic mice, TLK16998, at a dose of 10 mg/kg, lowered blood glucose levels for up to 6 h. These results suggest, therefore, that small nonpeptide molecules that directly sensitize the IR may be useful for treating type 2 diabetes.

Abbreviations: BSA, bovine serum albumin; CKD, cytoplasmic kinase domain; DEX, dexamethasone; EGF, epidermal growth factor; HFD, high-fat diet; IBMX, isobutylmethylxanthine; IR, insulin receptor; IRS-1, insulin receptor substrate 1; PBS, phosphate-buffered saline; PI, phosphatidylinositol; TLC, thin-layer chromatography

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