title: A novel small molecule that directly sensitizes the insulin receptor in vitro and in vivo.
abstract: 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 beta-subunit at concentrations of 1 micromol/l or less but had no effect on insulin binding to the IR alpha-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 micromol/l, enhanced the effects of insulin on the phosphorylation of the IR beta-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 beta-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 micromol/l and a 10-fold increase at 40 micromol/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.
authors: Telik, Inc., South San Francisco, California 94080, USA. manchem@telik.com
authors: V P
authors: VP
authors: Manchem
authors: I D
authors: ID
authors: Goldfine
authors: R A
authors: RA
authors: Kohanski
authors: C P
authors: CP
authors: Cristobal
authors: R T
authors: RT
authors: Lum
authors: S R
authors: SR
authors: Schow
authors: S
authors: S
authors: Shi
authors: W R
authors: WR
authors: Spevak
authors: E
authors: E
authors: Laborde
authors: D K
authors: DK
authors: Toavs
authors: H O
authors: HO
authors: Villar
authors: M M
authors: MM
authors: Wick
authors: M R
authors: MR
authors: Kozlowski
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D051275:Glucose Transporter Type 4; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D009281:Naphthalenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011972:Receptor, Insulin / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001391:Azo Compounds; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D009281:Naphthalenes; C495693:Slc2a4 protein, mouse; C423845:TLK 16998; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin