Inhibition of Src homology 2 domain containing protein tyrosine phosphatase as the possible mechanism of metformin-assisted amelioration of obesity induced insulin resistance in high fat diet fed C57BL/6J mice

Biochem Biophys Res Commun. 2017 May 20;487(1):54-61. doi: 10.1016/j.bbrc.2017.04.012. Epub 2017 Apr 5.


SHP-1 (Src homology 2 domain containing protein tyrosine phosphatase) is a known negative regulator of insulin signaling and inflammation. To date, the molecular mechanism of metformin in modulating SHP-1 expression has remained elusive. In the present study, we have investigated the role of SHP-1 in relation to anti-hyperglycemic and anti-inflammatory actions of metformin in an obese phenotype mouse model. We observed that metformin treatment significantly reduced SHP-1 activity in obese mice, leading to improved insulin sensitivity. Additionally, metformin down regulated inflammatory markers like TLR2, TLR4, CD80, CD86, NF-κB, STAT1 and suppressed adipose tissue inflammation by efficiently polarizing adipose tissue macrophages toward anti-inflammatory state by way of indirect inhibition of SHP-1 mRNA and protein expressions. Our study suggests that metformin exerts its insulin sensitizing effects via inhibition of SHP-1 activity and expression.

Keywords: Adipose tissue; Inflammation; Macrophages; Metformin; Obesity induced insulin resistance; SHP-1.

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism*
  • Animals
  • Diet, High-Fat
  • Dose-Response Relationship, Drug
  • Hypoglycemic Agents / administration & dosage
  • Inflammation Mediators / metabolism
  • Insulin Resistance*
  • Male
  • Metformin / administration & dosage*
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy*
  • Obesity / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*


  • Hypoglycemic Agents
  • Inflammation Mediators
  • Metformin
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse