Abstract: SA-PO128

A Novel SHIP2 Inhibitor Reduces the Catalytic Activity of SHIP2 in Kidney, Muscle, and Liver and Enhances Insulin Sensitivity

Session Information

Category: Diabetes

  • 503 Diabetes Mellitus and Obesity: Translational

Authors

  • Lehtonen, Sanna H., University of Helsinki, 00290 Helsinki, Finland
  • Tsuneki, Hiroshi, University of Toyama, Toyama, Japan
  • Sasaoka, Toshiyasu, University of Toyama, Toyama, Japan
  • Polianskyte-prause, Zydrune, University of Helsinki, 00290 Helsinki, Finland
  • Tolvanen, Tuomas Aleksi, University of Helsinki, 00290 Helsinki, Finland
  • Lindfors, Sonja, University of Helsinki, 00290 Helsinki, Finland
  • Kon, Kanta, University of Toyama, Toyama, Japan
  • Wang, Hong, University of Helsinki, 00290 Helsinki, Finland
  • Dumont, Vincent, University of Helsinki, 00290 Helsinki, Finland
  • Groop, Per-Henrik, Folkhälsan Institute of Genetics, Folkhälsan Research Center, University of Helsinki, Helsinki, Finland
  • Wada, Tsutomu, University of Toyama, Toyama, Japan
Background

The expression of lipid phosphatase SHIP2 is elevated in kidney, muscle and adipose tissues in experimental models of diabetes. Thus, SHIP2 is a potential therapeutic target to treat diabetic kidney injury and insulin resistance. To date, only few chemical compounds possessing an inhibitory effect on SHIP2 are known. All of them have poor bioavailability and none have reached clinical use.

Methods

To identify novel small molecules that inhibit SHIP2 we performed virtual screening of chemical libraries. The most potent SHIP2 inhibitors were validated by using recombinant SHIP2 fusion protein, cultured cells and diabetic db/db and SHIP2 overexpressing (SHIP2-Tg) mice.

Results

Virtual screening of chemical libraries containing 88680 molecules revealed compound II as a potential SHIP2 inhibitor. Compound II inhibits the catalytic activity of the recombinant SHIP2 phosphatase domain with an IC50 value of 0.75 µM. It also inhibits the activity of SHIP2 in cultured podocytes, myocytes and hepatocytes. Compound II increases glucose uptake in myocytes, and SHIP2 overexpression abrogates its insulin-mimetic properties. Treatment of SHIP2-Tg mice for 12 days with compound II reduces SHIP2 activity in kidney, skeletal muscle and liver and enhances insulin sensitivity. Treatment of db/db mice with compound II for 10 weeks enhances insulin sensitivity, decreases SHIP2 activity in the kidney and tends to reduce urinary albumin excretion.

Conclusion

Compound II inhibits the activity of SHIP2, enhances glucose uptake, and increases insulin sensitivity of both SHIP2-Tg and db/db mice. The db/db mice also show a trend of reduced albuminuria. This highlights the potential of SHIP2 as a drug target to treat diabetic kidney injury and insulin resistance. The data also propose that compound II and its derivatives have potential to be used for developing new insulin sensitizers.

Funding

  • Private Foundation Support