A liver-derived secretory protein, selenoprotein P, causes insulin resistance

Hirofumi Misu, Toshinari Takamura, Hiroaki Takayama, Hiroto Hayashi, Naoto Matsuzawa-Nagata, Seiichiro Kurita, Kazuhide Ishikura, Hitoshi Ando, Yumie Takeshita, Tsuguhito Ota, Masaru Sakurai, Tatsuya Yamashita, Eishiro Mizukoshi, Taro Yamashita, Masao Honda, Ken Ichi Miyamoto, Tetsuya Kubota, Naoto Kubota, Takashi Kadowaki, Han Jong KimIn Kyu Lee, Yasuhiko Minokoshi, Yoshiro Saito, Kazuhiko Takahashi, Yoshihiro Yamada, Nobuyuki Takakura, Shuichi Kaneko

Research output: Contribution to journalArticlepeer-review

427 Citations (Scopus)


The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral tissues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes.

Original languageEnglish
Pages (from-to)483-495
Number of pages13
JournalCell Metabolism
Issue number5
Publication statusPublished - 2010 Nov 3


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