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Reduction of PTP1B induces differential expression of PI3-kinase (p85alpha) isoforms

Cristina M Rondinone1, Jill Clampit, Rebecca J Gum

  • 1Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. cristina.rondinone@abbott.com

Biochemical and Biophysical Research Communications
|September 17, 2004
PubMed

Insights

Inhibition of Protein tyrosine phosphatase 1B (PTP1B) improves insulin sensitivity by altering PI3-kinase p85alpha isoforms in the liver. This reduction in p85alpha may be key to normalizing blood glucose levels in insulin resistance.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Metabolic Disease Research

Background:

  • Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of insulin signaling.
  • PTP1B inhibition enhances insulin sensitivity and glucose metabolism in animal models.
  • The precise molecular mechanisms underlying PTP1B's effects on insulin sensitivity are not fully understood.

Purpose of the Study:

  • To investigate the molecular events linking PTP1B inhibition to improved insulin sensitivity.
  • To examine the role of PTP1B in regulating PI3-kinase (PI3K) p85alpha isoforms in the liver.
  • To determine if differential regulation of p85alpha isoforms contributes to enhanced glucose metabolism.

Main Methods:

  • Administration of PTP1B antisense oligonucleotides to diabetic ob/ob mice.
  • In vitro transfection of mouse hepatocytes with PTP1B antisense or small interfering RNA (siRNA).
  • Assessment of PTP1B protein levels, p85alpha isoform expression (p85alpha, p50alpha, p55alpha), and insulin-induced PKB phosphorylation.

Main Results:

  • PTP1B inhibition in vivo and in vitro led to decreased PTP1B and p85alpha protein levels in liver and hepatocytes.
  • PTP1B inhibition resulted in altered expression of p85alpha isoforms, with reduced p85alpha and increased p50alpha and p55alpha.
  • Downregulation of p85alpha in hepatocytes enhanced insulin-stimulated protein kinase B (PKB) phosphorylation.

Conclusions:

  • PTP1B inhibition directly and differentially regulates p85alpha isoforms of PI3-kinase in the liver.
  • Reduction of p85alpha may represent a significant mechanism through which PTP1B inhibition improves insulin sensitivity.
  • These findings offer insights into potential therapeutic strategies for managing insulin resistance and type 2 diabetes.

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