title: Ras inhibition induces insulin sensitivity and glucose uptake.
abstract: BACKGROUND
  Reduced glucose uptake due to insulin resistance is a pivotal mechanism in the pathogenesis of type 2 diabetes. It is also associated with increased inflammation. Ras inhibition downregulates inflammation in various experimental models. The aim of this study was to examine the effect of Ras inhibition on insulin sensitivity and glucose uptake, as well as its influence on type 2 diabetes development.
  
  
  RESULTS
  The effect of Ras inhibition on glucose uptake was examined both in vitro and in vivo. Ras was inhibited in cells transfected with a dominant-negative form of Ras or by 5-fluoro-farnesylthiosalicylic acid (F-FTS), a small-molecule Ras inhibitor. The involvement of IκB and NF-κB in Ras-inhibited glucose uptake was investigated by immunoblotting. High fat (HF)-induced diabetic mice were treated with F-FTS to test the effect of Ras inhibition on induction of hyperglycemia. Each of the Ras-inhibitory modes resulted in increased glucose uptake, whether in insulin-resistant C2C12 myotubes in vitro or in HF-induced diabetic mice in vivo. Ras inhibition also caused increased IκB expression accompanied by decreased expression of NF-κB . In fat-induced diabetic mice treated daily with F-FTS, both the incidence of hyperglycemia and the levels of serum insulin were significantly decreased.
  
  
  CONCLUSIONS
  Inhibition of Ras apparently induces a state of heightened insulin sensitization both in vitro and in vivo. Ras inhibition should therefore be considered as an approach worth testing for the treatment of type 2 diabetes.
authors: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel-Aviv, Israel.
authors: Adi
authors: A
authors: Mor
authors: Elizabeta
authors: E
authors: Aizman
authors: Jacob
authors: J
authors: George
authors: Yoel
authors: Y
authors: Kloog
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D016133:Polymerase Chain Reaction; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D016283:Proto-Oncogene Proteins p21(ras); D005947:Glucose