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The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis

Marie-Julie Dubois1, Sébastien Bergeron, Hyo-Jeong Kim

  • 1Department of Anatomy-Physiology and Lipid Research Unit, Laval University Hospital Research Center, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.

Nature Medicine
|April 18, 2006
PubMed

Insights

Protein tyrosine phosphatase SHP-1 deficiency improves glucose tolerance and insulin sensitivity. This occurs due to enhanced insulin signaling in the liver and muscle, and increased hepatic insulin clearance.

Area of Science:

  • Biochemistry
  • Endocrinology
  • Molecular Biology

Background:

  • Protein tyrosine phosphatase SHP-1 (PTPN6) is a known inhibitor of signaling in hematopoietic cells.
  • Its role in insulin target tissues and glucose homeostasis remains largely unknown.

Purpose of the Study:

  • To investigate the role of SHP-1 in glucose homeostasis and insulin sensitivity in non-hematopoietic tissues.
  • To elucidate the molecular mechanisms underlying SHP-1's function in insulin signaling.

Main Methods:

  • Utilized viable motheaten (Ptpn6(me-v/me-v)) mice with deficient SHP-1 protein.
  • Employed adenoviral expression of a catalytically inert SHP-1 mutant and small hairpin RNA (shRNA) for SHP-1 silencing in wild-type mice.
  • Assessed insulin receptor signaling pathways (IRS-PI3K-Akt) in liver and muscle.
  • Measured tyrosine phosphorylation of CEACAM1 and serum insulin clearance rates in vitro and in vivo.

Main Results:

  • SHP-1 deficient mice exhibited significantly improved glucose tolerance and insulin sensitivity compared to wild-type littermates.
  • Enhanced insulin receptor signaling to IRS-PI3K-Akt was observed in the liver and muscle of SHP-1 deficient mice.
  • SHP-1 deficiency led to increased tyrosine phosphorylation of CEACAM1 and accelerated hepatic insulin clearance.
  • Experimental downregulation of SHP-1 activity mimicked these effects in normal mice.

Conclusions:

  • SHP-1 plays a novel inhibitory role in regulating glucose homeostasis.
  • Modulation of SHP-1 activity impacts insulin signaling in key metabolic tissues (liver and muscle).
  • SHP-1 influences hepatic insulin clearance, presenting a new therapeutic target for metabolic disorders.

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