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.