title: PEDF attenuates insulin-dependent molecular pathways of glucose homeostasis in skeletal myocytes.
abstract: Pigment epithelium-derived factor (PEDF) is an anti-angiogenic serpin associated with insulin resistance in metabolic disorders such as diabetes, metabolic syndrome, obesity and polycystic ovarian syndrome. While the mechanism of PEDF induced-insulin resistance of metabolic disorders has been attributed to its inflammatory and lipolytic effects, little evidence exists to support a direct role of PEDF in mediating insulin resistance. Here, we seminally provide evidence that PEDF can inhibit insulin signal transduction governing glucose homeostasis from the receptor to the effector phosphorylation through Akt/PKB-dependent and -independent pathways in mouse and human skeletal muscle cell lines. PEDF attenuates the insulin-dependent molecular axes of glucose metabolism. Exposure of skeletal myocytes to PEDF attenuates insulin-dependent insulin receptor autophosphorylation, tyrosine phosphorylation of insulin receptor substrate 1, and dual loop phosphorylation-activation of Akt. PEDF significantly inhibits the downstream effector - glycogen synthase kinase (and thereby the glycogenic axis of insulin signalling). PEDF turned off both the molecular switches of GLUT4 translocation: IRS-Akt/PKB-AS160 mediated and IR-pCbl-dependent GLUT4 translocation (the molecular axis of glucose uptake). These findings implicate a direct effect of PEDF on multiple insulin-dependent molecular mechanisms of glucose homeostasis in skeletal muscle cells, thereby enabling it to contribute to peripheral insulin resistance at the cellular level.
authors.affiliation: Curtin Biosciences Research Precinct, Bentley, 6102, Australia; School of Pharmacy, Curtin University, Bentley, 6102, Australia.
authors.forename: Revathy
authors.initials: R
authors.lastname: Carnagarin
authors.affiliation: Curtin Biosciences Research Precinct, Bentley, 6102, Australia; School of Biomedical Science, Curtin University, Bentley, 6102, Australia.
authors.forename: Arun M
authors.initials: AM
authors.lastname: Dharmarajan
authors.affiliation: Curtin Biosciences Research Precinct, Bentley, 6102, Australia; School of Pharmacy, Curtin University, Bentley, 6102, Australia. Electronic address: Crispin.Dass@curtin.edu.au.
authors.forename: Crispin R
authors.initials: CR
authors.lastname: Dass
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005136:Eye Proteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism*; D015398:Signal Transduction; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D005947:Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor
keywords: Akt; Glucose; Insulin resistance; PEDF; Skeletal muscle