title: Effect of insulin on the soluble receptor for advanced glycation end products (RAGE).
abstract: OBJECTIVE
  The receptor for advanced glycation end products (RAGE) plays an important role in the pathogenesis of diabetic complications. RAGE transcript splicing generates a number of isoforms, including a full-length membrane-bound receptor and a soluble isoform, endogenous secretory RAGE (esRAGE). Soluble forms of the receptor (sRAGE) can also be formed by ectodomain shedding of the membrane-associated receptor. We have evaluated serum levels of sRAGE and esRAGE in Chinese patients with Type 1 diabetes and investigated the effect of insulin on the generation of esRAGE and sRAGE in vitro.
  
  
  METHODS
  Serum sRAGE and esRAGE were measured by ELISA. The in vitro effect of insulin was investigated by incubating THP-1 macrophages with insulin and RAGE isoforms in cell lysate and conditioned media determined.
  
  
  RESULTS
  In patients with diabetes, both serum esRAGE and sRAGE were significantly higher than in age-matched healthy subjects without diabetes. In vitro, insulin increased esRAGE and total RAGE isoform expression in cell lysate on a western blot, and reverse transcription-polymerase chain reaction showed an increase in esRAGE and full-length RAGE mRNA. This was accompanied by an increase in esRAGE and sRAGE in cell conditioned media. Pretreatment of THP-1 cells with a general metalloproteinase inhibitor GM6001 significantly reduced the production of sRAGE, suggesting that insulin also increased the cleavage of full-length cell surface RAGE to form sRAGE.
  
  
  CONCLUSIONS
  Chinese patients with Type 1 diabetes have higher serum levels of esRAGE and sRAGE. In vitro, insulin not only increases both full-length RAGE and esRAGE expression, but can also stimulate the shedding of sRAGE from the membrane-bound receptor.
authors: Department of Medicine, University of Hong Kong, Hong Kong.
authors: J K Y
authors: JK
authors: Lam
authors: Y
authors: Y
authors: Wang
authors: S W M
authors: SW
authors: Shiu
authors: Y
authors: Y
authors: Wong
authors: D J
authors: DJ
authors: Betteridge
authors: K C B
authors: KC
authors: Tan
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002681:China; D003430:Cross-Sectional Studies; D017077:Culture Media, Conditioned / Q000737:chemistry; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008875:Middle Aged; D020033:Protein Isoforms / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D017077:Culture Media, Conditioned; D007004:Hypoglycemic Agents; D007328:Insulin; D061965:Matrix Metalloproteinase Inhibitors; D020033:Protein Isoforms; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic