title: Inhibition of Src homology 2 domain-containing phosphatase 1 increases insulin sensitivity in high-fat diet-induced insulin-resistant mice.
abstract: 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.
authors.affiliation: Center for Cardiovascular Research/CCR Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry Charité - Universitätsmedizin Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Krüger
authors.affiliation: Department of Medicine/Cardiology Deutsches Herzzentrum Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Wellnhofer
authors.affiliation: Department of Medicine/Cardiology Deutsches Herzzentrum Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Meyborg
authors.affiliation: Department of Medicine/Cardiology Deutsches Herzzentrum Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
authors.affiliation: Cancer Center Karolinska Karolinska Institutet Stockholm Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
authors.affiliation: Center for Cardiovascular Research/CCR Institute of Pharmacology Charité - Universitätsmedizin Berlin Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.affiliation: Center for Cardiovascular Research/CCR Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry Charité - Universitätsmedizin Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
keywords: PTP inhibition; SHP‐1/Ptpn6; bis(maltolato)oxovanadium(IV); insulin resistance; protein tyrosine phosphatases; sodium stibogluconate