title: Pyrroloquinoline quinone, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves impaired glucose tolerance in diabetic KK-A(y) mice.
abstract: Insulin resistance is a pathological hallmark of type 2 diabetes mellitus and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor, and increased activity and expression of PTP1B is implicated in the pathogenesis of insulin resistance. Therefore, inhibition of PTP1B is anticipated to improve insulin resistance in type 2 diabetic subjects. Pyrroloquinoline quinone (PQQ), a redox cofactor for bacterial dehydrogenases, inhibits PTP1B to oxidatively modify the catalytic cysteine through its redox cycling activity. Here, we report that PQQ induces the ligand-independent activation of insulin signaling by inhibiting cellular PTP1B and enhances glucose uptake through the translocation of glucose transporter 4 in mouse C2C12 myotubes. Furthermore, we demonstrated that oral administration of PQQ improved impaired glucose tolerance in type 2 diabetic KK-A(y) mice. Our results strongly suggest that PQQ can be useful in anti-diabetic treatment for type 2 diabetic subjects.
authors.affiliation: Department of Biological Chemistry, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai 599-8531, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Takada
authors.forename: Mika
authors.initials: M
authors.lastname: Sumi
authors.forename: Ayumi
authors.initials: A
authors.lastname: Maeda
authors.forename: Fumiko
authors.initials: F
authors.lastname: Watanabe
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kamiya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishii
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nakano
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Akagawa
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000201:enzymology*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D045542:PQQ Cofactor / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; D007328:Insulin; D045542:PQQ Cofactor; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1