title: Insulin-mediated activation of the L-arginine nitric oxide pathway in man, and its impairment in diabetes.
abstract: OBJECTIVE
  Impaired L-arginine transport has been reported in cardiovascular diseases, providing a possible mechanism for reduced nitric oxide (NO) production. Given that cardiovascular diseases are also associated with insulin resistance, and insulin is known to induce vasodilation via a NO-dependent pathway, we hypothesised that abnormal insulin modulation of L-arginine transport may contribute to vascular dysfunction in diabetes.
  
  
  METHODS
  Forearm blood flow (FBF) responses to insulin and sodium nitroprusside (SNP) were measured in control and type 2 diabetic volunteers using venous occlusion plethysmography. Effects of intra-arterial insulin on the forearm veno-arterial flux of arginine and related amino acids were determined by HPLC. The effect of locally delivered insulin on arginine transport was assessed during an intra-arterial infusion of [4,5-(3)H] L-arginine.
  
  
  RESULTS
  In controls, intrabrachial infusion of 5 mUnits/min insulin lead to a progressive rise in FBF (p<0.001) while this was not evident in diabetics. In support of this observation, we observed a concomitant, significant increase in the flux of N-hydroxy-L-arginine (the NO precursor) in controls (baseline vs. 60 mins insulin: 16.2±12.2 vs. 33.0±13.1 nmol/100 ml tissue/min; p<0.01), whilst no increase was observed in diabetics. Moreover, insulin augmented the clearance of [(3)H]L-arginine from the forearm circulation in controls (baseline vs insulin: 123±22 vs. 150±28 ml/min; p<0.05) but not in diabetics.
  
  
  CONCLUSIONS
  These findings suggest that insulin resistance may contribute substantially to the onset and development of cardiovascular disease in type 2 diabetics via abnormal insulin-mediated regulation of L-arginine transport.
authors: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors: Niwanthi W
authors: NW
authors: Rajapakse
authors: Abigail L
authors: AL
authors: Chong
authors: Wei-Zheng
authors: WZ
authors: Zhang
authors: David M
authors: DM
authors: Kaye
mesh_terms: D000328:Adult; D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D007328:Insulin; D009599:Nitroprusside; D009569:Nitric Oxide; D001120:Arginine
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