title: Regulation of insulin receptor function by a small molecule insulin receptor activator.
abstract: 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) beta-subunit tyrosine kinase. In HTC-IR cells, 20 microm 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 microm 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.
authors.affiliation: Mount Zion Medical Center, University of California, San Francisco 94143-1616, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: Pender
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.forename: Vara Prasad
authors.initials: VP
authors.lastname: Manchem
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Evans
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Spevak
authors.forename: Songyuan
authors.initials: S
authors.lastname: Shi
authors.forename: Sandhya
authors.initials: S
authors.lastname: Rao
authors.forename: Sonia
authors.initials: S
authors.lastname: Bajjalieh
authors.forename: Betty A
authors.initials: BA
authors.lastname: Maddux
authors.forename: Jack F
authors.initials: JF
authors.lastname: Youngren
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D010766:Phosphorylation; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism* / Q000502:physiology*; D013425:Sulfanilic Acids / Q000494:pharmacology; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D013425:Sulfanilic Acids; C469742:TLK 19780; D014443:Tyrosine; D014508:Urea; D011972:Receptor, Insulin; D005947:Glucose