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Protein tyrosine phosphatase regulation in fibroblasts from patients with an insulin receptor gene mutation

N Seki1, S Yagi, Y Suzuki

  • 1Clinical Research Center, National Hospital Organization, Chiba-East National Hospital, Chiba, Japan.

Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme
|October 18, 2008
PubMed

Insights

Insulin receptor gene mutations in fibroblasts reduce protein tyrosine phosphatase (PTPase) activity. This blunts the response to insulin, suggesting a distinct mechanism in severe insulin resistance compared to type 2 diabetes.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Endocrinology

Background:

  • Insulin receptor (IR) activation initiates signaling via tyrosine phosphorylation.
  • Protein tyrosine phosphatases (PTPases) counteract insulin signaling and are linked to insulin resistance.
  • Protein tyrosine phosphatase 1B (PTP1B) and leukocyte antigen-related PTPase (LAR) are key PTPases implicated in diabetes.

Purpose of the Study:

  • To investigate PTP1B and LAR expression in human fibroblasts.
  • To examine PTPase activity regulation in fibroblasts from patients with insulin receptor gene mutations.
  • To establish an in vitro model for studying insulin resistance.

Main Methods:

  • Assessed PTP1B and LAR expression in human fibroblasts.
  • Measured total PTPase activity in cytosolic and membrane fractions.
  • Analyzed PTPase activity following insulin stimulation in mutant versus wild-type fibroblasts.

Main Results:

  • PTP1B and LAR were expressed in human fibroblasts.
  • Total PTPase activity was significantly lower in fibroblasts with insulin receptor mutations.
  • Insulin stimulation caused a smaller increase in PTP1B activity in mutant fibroblasts compared to controls.

Conclusions:

  • Insulin receptor gene mutations impair PTPase activity regulation in response to insulin.
  • This impairment may involve a negative feedback mechanism.
  • PTPase activity profiles in patients with insulin receptor gene mutations and severe insulin resistance may differ from type 2 diabetes.

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