title: NADPH oxidase inhibition prevents beta cell dysfunction induced by prolonged elevation of oleate in rodents.
abstract: OBJECTIVE
  The activation of NADPH oxidase has been implicated in NEFA-induced beta cell dysfunction. However, the causal role of this activation in vivo remains unclear. Here, using rodents, we investigated whether pharmacological or genetic inhibition of NADPH oxidase could prevent NEFA-induced beta cell dysfunction in vivo.
  
  
  METHODS
  Normal rats were infused for 48 h with saline or oleate with or without the NADPH oxidase inhibitor apocynin. In addition, NADPH oxidase subunit p47(phox)-null mice and wild-type littermate controls were infused with saline or oleate for 48 h. This was followed by measurement of NADPH oxidase activity, reactive oxygen species (ROS) and superoxide imaging and assessment of beta cell function in isolated islets and hyperglycaemic clamps.
  
  
  RESULTS
  Oleate infusion in rats increased NADPH oxidase activity, consistent with increased total but not mitochondrial superoxide in islets and impaired beta cell function in isolated islets and during hyperglycaemic clamps. Co-infusion of apocynin with oleate normalised NADPH oxidase activity and total superoxide levels and prevented beta cell dysfunction. Similarly, 48 h NEFA elevation in wild-type mice increased total but not mitochondrial superoxide and impaired beta cell function in isolated islets. p47(phox)-null mice were protected against these effects when subjected to 48 h oleate infusion. Finally, oleate increased the levels of total ROS, in both models, whereas inhibition of NADPH oxidase prevented this increase, suggesting that NADPH oxidase is the main source of ROS in this model.
  
  
  CONCLUSIONS
  These data show that NADPH-oxidase-derived cytosolic superoxide is increased in islets upon oleate infusion in vivo; and whole-body NADPH-oxidase inhibition decreases superoxide in concert with restoration of islet function.
authors: Department of Physiology, University of Toronto, Medical Sciences Building, Room 3336-1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors: K
authors: K
authors: Koulajian
authors: T
authors: T
authors: Desai
authors: G C
authors: GC
authors: Liu
authors: A
authors: A
authors: Ivovic
authors: J N
authors: JN
authors: Patterson
authors: C
authors: C
authors: Tang
authors: J
authors: J
authors: El-Benna
authors: J W
authors: JW
authors: Joseph
authors: J W
authors: JW
authors: Scholey
authors: A
authors: A
authors: Giacca
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D007262:Infusions, Intravenous; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019301:Oleic Acid / Q000008:administration & dosage / Q000009:adverse effects; D018384:Oxidative Stress; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D019301:Oleic Acid; C056165:acetovanillone; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1