Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance

Insulin resistance is a major disorder that links obesity to type 2 diabetes mellitus (T2D). It involves defects in the insulin actions owing to a reduced ability of insulin to trigger key signaling pathways in major metabolic tissues. The pathogenesis of insulin resistance involves several inhibitory molecules that interfere with the tyrosine phosphorylation of the insulin receptor and its downstream effectors. Among those, growing interest has been developed toward the protein tyrosine phosphatases (PTPs), a large family of enzymes that can inactivate crucial signaling effectors in the insulin signaling cascade by dephosphorylating their tyrosine residues. Herein we briefly review the role of several PTPs that have been shown to be implicated in the regulation of insulin action, and then focus on the Src homology 2 (SH2) domain-containing SHP1 and SHP2 enzymes, since recent reports have indicated major roles for these PTPs in the control of insulin action and glucose metabolism. Finally, the therapeutic potential of targeting PTPs for combating insulin resistance and alleviating T2D will be discussed.