Reduction of Protein Tyrosine Phosphatase 1B Increases Insulin-Dependent Signaling in ob/ob Mice

  1. Rebecca J. Gum1,
  2. Lori L. Gaede2,
  3. Sandra L. Koterski1,
  4. Matthew Heindel3,
  5. Jill E. Clampit1,
  6. Bradley A. Zinker1,
  7. James M. Trevillyan1,
  8. Roger G. Ulrich2,
  9. Michael R. Jirousek1 and
  10. Cristina M. Rondinone1
  1. 1Metabolic Disease Research, Abbott Laboratories, Abbott Park, Illinois
  2. 2Investigative Toxicology, Abbott Laboratories, Abbott Park, Illinois
  3. 3Cellular and Molecular Toxicology, Abbott Laboratories, Abbott Park, Illinois

    Abstract

    Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin receptor (IR) signal transduction and a drug target for treatment of type 2 diabetes. Using PTP1B antisense oligonucleotides (ASOs), effects of decreased PTP1B levels on insulin signaling in diabetic ob/ob mice were examined. Insulin stimulation, prior to sacrifice, resulted in no significant activation of insulin signaling pathways in livers from ob/ob mice. However, in PTP1B ASO-treated mice, in which PTP1B protein was decreased by 60% in liver, similar stimulation with insulin resulted in increased tyrosine phosphorylation of the IR and IR substrate (IRS)-1 and -2 by threefold, fourfold, and threefold, respectively. IRS-2-associated phosphatidylinositol 3-kinase activity was also increased threefold. Protein kinase B (PKB) serine phosphorylation was increased sevenfold in liver of PTP1B ASO-treated mice upon insulin stimulation, while phosphorylation of PKB substrates, glycogen synthase kinase (GSK)-3α and -3β, was increased more than twofold. Peripheral insulin signaling was increased by PTP1B ASO, as evidenced by increased phosphorylation of PKB in muscle of insulin-stimulated PTP1B ASO-treated animals despite the lack of measurable effects on muscle PTP1B protein. These results indicate that reduction of PTP1B is sufficient to increase insulin-dependent metabolic signaling and improve insulin sensitivity in a diabetic animal model.

    Footnotes

    • Address correspondence and reprint requests to Rebecca J. Gum, Abbott Laboratories, R-4MJ, AP10-1, 100 Abbott Park Rd., Abbott Park, IL 60064-3502. E-mail: rebecca.gum{at}abbott.com.

      Received for publication 3 May 2002 and accepted in revised form 14 October 2002.

      R.G.U. and M.R.J. were formerly employed by Abbott Laboratories. R.G.U. is currently employed by Rosetta Inpharmatics, a subsidiary of Merck, and holds stock in Abbott Laboratories and Pharmacia. M.R.J. is currently employed by Pfizer Global R&D and holds stock in Abbott Laboratories, Pfizer, and Eli Lilly.

      ASO, antisense oligonucleotide; ECL, enhanced chemiluminescence; GSK, glycogen synthase kinase; IR, insulin receptor; IRS, IR substrate; PEPCK, phosphoenolpyruvate carboxykinase; PI, phosphatidylinositol; PKB, protein kinase B; PTP1B, protein tyrosine phosphatase 1B.

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