title: Cellular chromium enhances activation of insulin receptor kinase.
abstract: Chromium has been recognized for decades as a nutritional factor that improves glucose tolerance by enhancing in vivo insulin action, but the molecular mechanism is unknown. Here we report pretreatment of CHO-IR cells with chromium enhances tyrosine phosphorylation of the insulin receptor. Different chromium(III) compounds were effective at enhancing insulin receptor phosphorylation in intact cells, but did not directly activate recombinant insulin receptor kinase. The level of insulin receptor phosphorylation in cells can be increased by inhibition of the opposing protein tyrosine phosphatase (PTP1B), a target for drug development. However, chromium did not inhibit recombinant human PTP1B using either p-nitrophenyl phosphate or the tyrosine-phosphorylated insulin receptor as the substrate. Chromium also did not alter reversible redox regulation of PTP1B. Purified plasma membranes exhibited insulin-dependent kinase activity in assays using substrate peptides mimicking sites of Tyr phosphorylation in the endogenous substrate IRS-1. Plasma membranes prepared from chromium-treated cells had higher specific activity of insulin-dependent kinase relative to controls. We conclude that cellular chromium potentiates insulin signaling by increasing insulin receptor kinase activity, separate from inhibition of PTPase. Our results suggest that nutritional and pharmacological therapies may complement one another to combat insulin resistance, a hallmark of type 2 diabetes.
authors.affiliation: Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0577, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Allison
authors.initials: A
authors.lastname: Kruszewski
authors.forename: David L
authors.initials: DL
authors.lastname: Brautigan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D002857:Chromium / Q000737:chemistry* / Q000502:physiology; D006224:Cricetinae; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D011993:Recombinant Fusion Proteins; D002857:Chromium; D014443:Tyrosine; D005982:Glutathione Transferase; D011972:Receptor, Insulin; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases