title: Decreased IRS2 and TIMP3 expression in monocytes from offspring of type 2 diabetic patients is correlated with insulin resistance and increased intima-media thickness.
abstract: OBJECTIVE
  In humans, it is unclear if insulin resistance at the monocyte level is associated with atherosclerosis in vivo. Here we have studied first-degree relatives of patients with type 2 diabetes to investigate whether a reduction in components of the insulin signal transduction pathways, such as the insulin receptor (InsR) or InsR substrate 1 or 2 (IRS1 or IRS2), or a reduction in genetic modifiers of insulin action, such as the TIMP3/ADAM17 (tissue inhibitor of metalloproteinase 3/A disintegrin and metalloprotease domain 17) pathway, is associated with evidence of atherosclerosis.
  
  
  METHODS
  Insulin sensitivity was analyzed through euglycemic-hyperinsulinemic clamp, and subclinical atherosclerosis was analyzed through intimal medial thickness. Monocytes were isolated through magnetic cell sorting, and mRNA and proteins were extracted and analyzed by quantitative PCR and pathscan enzyme-linked immunosorbent assays, respectively.
  
  
  RESULTS
  In monocyte cells from human subjects with increased risk for diabetes and atherosclerosis, we found that gene expression, protein levels, and tyrosine phosphorylation of IRS2, but not InsR or IRS1, were decreased. TIMP3 was also reduced, along with insulin resistance, resulting in increased ectodomain shedding activity of the metalloprotease ADAM17.
  
  
  CONCLUSIONS
  Systemic insulin resistance and subclinical atherosclerosis are associated with decreased IRS2 and TIMP3 expression in circulating monocytes.
authors: Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
authors: Marina
authors: M
authors: Cardellini
authors: Rossella
authors: R
authors: Menghini
authors: Alessio
authors: A
authors: Luzi
authors: Francesca
authors: F
authors: Davato
authors: Iris
authors: I
authors: Cardolini
authors: Rossella
authors: R
authors: D'Alfonso
authors: Paolo
authors: P
authors: Gentileschi
authors: Stefano
authors: S
authors: Rizza
authors: Maria Adelaide
authors: MA
authors: Marini
authors: Ottavia
authors: O
authors: Porzio
authors: Davide
authors: D
authors: Lauro
authors: Paolo
authors: P
authors: Sbraccia
authors: Renato
authors: R
authors: Lauro
authors: Massimo
authors: M
authors: Federici
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000378:metabolism; D059168:Carotid Intima-Media Thickness; D003924:Diabetes Mellitus, Type 2; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3