Inhibition of Src homology 2 domain‐containing phosphatase 1 increases insulin sensitivity in high‐fat diet‐induced insulin‐resistant mice

Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain‐containing phosphatase 1 (SHP‐1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high‐fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low‐fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD‐fed mice were pharmacologically treated with the SHP‐1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan‐PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA‐mediated SHP‐1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP‐1 was capable of dephosphorylating the ligand‐induced tyrosine‐phosphorylated insulin receptor. These results indicate a central role of SHP‐1 in insulin signalling during obesity, and SHP‐1 inhibition as a potential therapeutic approach in metabolic diseases.