title: Role of plasminogen activator inhibitor-1 in glucocorticoid-induced diabetes and osteopenia in mice.
abstract: Long-term use of glucocorticoids (GCs) causes numerous adverse effects, including glucose/lipid abnormalities, osteoporosis, and muscle wasting. The pathogenic mechanism, however, is not completely understood. In this study, we used plasminogen activator inhibitor-1 (PAI-1)-deficient mice to explore the role of PAI-1 in GC-induced glucose/lipid abnormalities, osteoporosis, and muscle wasting. Corticosterone markedly increased the levels of circulating PAI-1 and the PAI-1 mRNA level in the white adipose tissue of wild-type mice. PAI-1 deficiency significantly reduced insulin resistance and glucose intolerance but not hyperlipidemia induced by GC. An in vitro experiment revealed that active PAI-1 treatment inhibits insulin-induced phosphorylation of Akt and glucose uptake in HepG2 hepatocytes. However, this was not observed in 3T3-L1 adipocytes and C2C12 myotubes, indicating that PAI-1 suppressed insulin signaling in hepatocytes. PAI-1 deficiency attenuated the GC-induced bone loss presumably via inhibition of apoptosis of osteoblasts. Moreover, the PAI-1 deficiency also protected from GC-induced muscle loss. In conclusion, the current study indicated that PAI-1 is involved in GC-induced glucose metabolism abnormality, osteopenia, and muscle wasting in mice. PAI-1 may be a novel therapeutic target to mitigate the adverse effects of GC.
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kawao
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.affiliation: Life Science Research Institute, Kinki University, Osakasayama, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Okumoto
authors.affiliation: Clinical Research Center, Kinki University Hospital, Osakasayama, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Chiba
authors.affiliation: Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsuo
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Japan hkaji@med.kindai.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaji
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000139:chemically induced* / Q000378:metabolism*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006474:Hemorrhagic Disorders / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D005938:Glucocorticoids; D017395:Plasminogen Activator Inhibitor 1