A Liver-Derived Secretory Protein, Selenoprotein P, Causes Insulin Resistance

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (169 K)Download as PowerPoint slideHighlights► SeP emerged from human liver screen for hepatokines involved in insulin resistance ► Glucose or palmitate increases SeP mRNA, whereas insulin decreases it in hepatocytes ► SeP induces insulin resistance in liver and muscle, resulting in hyperglycemia ► SeP dephosphorylates AMPK in hepatocytes in an AMP/ATP ratio-independent manner