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Developmental switch from prolonged insulin action to increased insulin sensitivity in protein tyrosine phosphatase

Agueda Gonzalez-Rodriguez1, Jill E Clampit, Oscar Escribano

  • 1Instituto de Investigaciones Biomédicas Alberto Sols (Centro mixto Consejo Superior de Investigaciones Cientificas/Universidad Autónoma), C/Arturo Duperier 4, 28029 Madrid, Spain. avalverde@iib.uam.es

Endocrinology
|October 28, 2006
PubMed

Insights

Protein tyrosine phosphatase 1B (PTP1B) deficiency improves insulin sensitivity in adult mice by altering insulin receptor and phosphatidylinositol 3-kinase signaling. This enhanced hepatic insulin sensitivity is acquired postnatally.

Area of Science:

  • Metabolism and Endocrinology
  • Cellular Biology
  • Diabetes Research

Background:

  • Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling.
  • PTP1B is a potential therapeutic target for type 2 diabetes.
  • Understanding PTP1B's role in insulin sensitivity across different life stages is crucial.

Purpose of the Study:

  • To investigate age-dependent differences in insulin sensitivity in hepatocytes lacking PTP1B.
  • To compare insulin signaling pathways in neonatal versus adult PTP1B-deficient hepatocytes.
  • To elucidate the molecular mechanisms underlying PTP1B's impact on hepatic insulin sensitivity.

Main Methods:

  • Generation of immortalized and primary hepatocytes from PTP1B(-/-) and wild-type mice (neonatal and adult).
  • Analysis of insulin-induced tyrosine phosphorylation of insulin receptor (IR) and IR substrates (IRS).
  • Assessment of phosphatidylinositol 3-kinase/Akt pathway activation and gluconeogenic gene expression.

Main Results:

  • PTP1B deficiency prolonged insulin signaling in neonatal hepatocytes but did not alter overall insulin sensitivity.
  • Adult PTP1B-deficient hepatocytes showed enhanced Akt phosphorylation and greater inhibition of gluconeogenic mRNAs.
  • Down-regulation of p85alpha and altered IR/IRS-2 expression were observed in adult PTP1B-deficient livers.

Conclusions:

  • Hepatic insulin sensitivity acquired through PTP1B deficiency is a postnatal developmental process.
  • Changes in IR and IRS-2 expression are key to insulin sensitization in adult PTP1B-deficient hepatocytes.
  • Altered balance of phosphatidylinositol 3-kinase subunits contributes to enhanced insulin sensitivity in adults.

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