Best Practice & Research Clinical Endocrinology & Metabolism
Volume 21, Issue 4 , Pages 621-640, December 2007

Inhibition of the protein tyrosine phosphatase PTP1B: potential therapy for obesity, insulin resistance and type-2 diabetes mellitus

  • Shlomit Koren, MD (Research Fellow, Internal Medicine and Endocrinology and Metabolism, Department of Medicine and Banting and Best Diabetes Center, University of Toronto)
  • I. George Fantus, MD, FRCP(C) (Professor, Department of Medicine and Physiology and Director, Division of Endocrinology and Metabolism, University of Toronto)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: 416 586 8665; Fax: 416 361 2657.

Department of Medicine, Mount Sinai Hospital, University Health Network, University of Toronto, Lebovic Building, 60 Murray Street, 5th Floor, Room 5028, Toronto, Ontario M5T 3L9, Canada

Department of Physiology, and The Banting and Best Diabetes Centre, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada

The global epidemic of obesity and type-2 diabetes mellitus (T2DM) has highlighted the need for new therapeutic approaches. The association of insulin resistance with these disorders and the knowledge that insulin receptor signaling is mediated by tyrosine (Tyr) phosphorylation have generated great interest in the regulation of the balance between Tyr phosphorylation and dephosphorylation. Several protein Tyr phosphatases (PTPs) have been implicated in the regulation of insulin action, with the most convincing data for PTP1B. Murine models targeting PTP1B, PTP1B−/−mice, demonstrate enhanced insulin sensitivity without the weight gain seen with other insulin sensitizers such as peroxisome proliferator-activated receptor γ (PPARγ) agonists, probably due to a second action of PTP1B as a negative regulator of leptin signaling. Despite intensive efforts and recent progress, a safe, selective and efficacious PTP1B inhibitor has yet to be identified.

Key words: protein tyrosine phosphatases, insulin signalling, PTPlB, type-2 diabetes, mellitus, leptin

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PII: S1521-690X(07)00081-4

doi:10.1016/j.beem.2007.08.004

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 21, Issue 4 , Pages 621-640, December 2007

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