title: Reduced skeletal muscle secreted frizzled-related protein 3 is associated with inflammation and insulin resistance.
abstract: To investigate the role of secreted frizzled-related protein 3 (Sfrp3) in insulin sensitivity (ISi) and β-cell function in humans across a spectrum of glucose homeostasis.
  
  
  
  Subjects included those with normal glucose homeostasis (NGT; n = 18), prediabetes (PD; n = 11), or type 2 diabetes (T2D; n=12). Serum and skeletal muscle (SkM) Sfrp3 levels were measured by ELISA and qPCR, respectively, and insulin signaling pathway was assessed by Western blot. IS and β-cell function were assessed by indices derived from frequently sampled intravenous glucose tolerance test.
  
  
  
  SkM Sfrp3 mRNA levels were significantly reduced in PD and T2D versus NGT. Similarly, serum Sfrp3 levels tended to be decreased in PD and T2D versus NGT. SkM Sfrp3 mRNA levels correlated negatively with circulating proinflammatory cytokines (IL-6, IFN-γ) and positively with IS. In vitro-differentiated myotubes from lean insulin-sensitive subjects treated with either lipopolysaccharide (LPS) or recombinant IL-6 demonstrated a dose-dependent reduction in Sfrp3 gene expression. Treatment of myotubes with recombinant Sfrp3 restored LPS- and IL-6-induced attenuation of insulin-stimulated Akt phosphorylation.
  
  
  
  Inflammation-induced reduction in SkM Sfrp3 expression may contribute to insulin resistance, and this effect may be prevented by addition of exogenous Sfrp3. Thus, Sfrp3 may be a novel target for insulin sensitization.
authors.affiliation: Translational Research Institute for Metabolism and Diabetes at Florida Hospital, Orlando, Florida, USA.
authors.forename: Alok S
authors.initials: AS
authors.lastname: Pachori
authors.affiliation: Translational Research Institute for Metabolism and Diabetes at Florida Hospital, Orlando, Florida, USA.
authors.forename: Meenu
authors.initials: M
authors.lastname: Madan
authors.affiliation: Translational Research Institute for Metabolism and Diabetes at Florida Hospital, Orlando, Florida, USA.
authors.forename: Yury O
authors.initials: YO
authors.lastname: Nunez Lopez
authors.affiliation: Translational Research Institute for Metabolism and Diabetes at Florida Hospital, Orlando, Florida, USA.
authors.forename: Fanchao
authors.initials: F
authors.lastname: Yi
authors.affiliation: Translational Research Institute for Metabolism and Diabetes at Florida Hospital, Orlando, Florida, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Translational Research Institute for Metabolism and Diabetes at Florida Hospital, Orlando, Florida, USA.|Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA.|Chemical Engineering Department, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Attila A
authors.initials: AA
authors.lastname: Seyhan
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000502:physiology; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011236:Prediabetic State / Q000188:drug therapy / Q000503:physiopathology*; D011506:Proteins / Q000378:metabolism* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D001786:Blood Glucose; D007328:Insulin; D007371:Interferon-gamma; D015850:Interleukin-6; D011506:Proteins; D012333:RNA, Messenger; D000094742:Secreted Frizzled-Related Proteins