title: Amelioration of Diabetes by Protein S.
abstract: Protein S is an anticoagulant factor that also regulates inflammation and cell apoptosis. The effect of protein S on diabetes and its complications is unknown. This study compared the development of diabetes between wild-type and transgenic mice overexpressing human protein S and the development of diabetic glomerulosclerosis between mice treated with and without human protein S and between wild-type and protein S transgenic mice. Mice overexpressing protein S showed significant improvements in blood glucose level, glucose tolerance, insulin sensitivity, and insulin secretion compared with wild-type counterparts. Exogenous protein S improved insulin sensitivity in adipocytes, skeletal muscle, and liver cell lines in db/db mice compared with controls. Significant inhibition of apoptosis with increased expression of BIRC3 and Bcl-2 and enhanced activation of Akt/PKB was induced by protein S in islet β-cells compared with controls. Diabetic wild-type mice treated with protein S and diabetic protein S transgenic mice developed significantly less severe diabetic glomerulosclerosis than controls. Patients with type 2 diabetes had significantly lower circulating free protein S than healthy control subjects. This study shows that protein S attenuates diabetes by inhibiting apoptosis of β-cells and the development of diabetic nephropathy.
authors.affiliation: Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yasuma
authors.affiliation: Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yano
authors.affiliation: Department of Immunology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Corina N
authors.initials: CN
authors.lastname: D'Alessandro-Gabazza
authors.affiliation: Department of Immunology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
authors.affiliation: Department of Immunology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Paloma
authors.initials: P
authors.lastname: Gil-Bernabe
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Nishihama
authors.affiliation: Department of Immunology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Hinneh
authors.affiliation: Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Rumi
authors.initials: R
authors.lastname: Mifuji-Moroka
authors.affiliation: Department of Immunology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Ziaurahman
authors.initials: Z
authors.lastname: Roeen
authors.affiliation: Division of Hematology, Stanford School of Medicine, Stanford, CA.
authors.forename: John
authors.initials: J
authors.lastname: Morser
authors.affiliation: Carl R. Woese Institute for Genomic Biology Institute for Genomic Biology and Department of Animal Sciences and Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL.
authors.forename: Isaac
authors.initials: I
authors.lastname: Cann
authors.affiliation: Department of Immunology, Mie University Graduate School of Medicine, Edobashi, Japan Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Iwasa
authors.initials: I
authors.lastname: Motoh
authors.affiliation: Department of Diabetes, Metabolism and Endocrinology, Mie University Graduate School of Medicine, Edobashi, Japan Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Edobashi, Japan Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Edobashi, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei
authors.affiliation: Department of Immunology, Mie University Graduate School of Medicine, Edobashi, Japan gabazza@doc.medic.mie-u.ac.jp.
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Gabazza
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D017293:Protein S / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D017293:Protein S