title: Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) activation in rat muscle, in the absence of mitochondrial dysfunction.
abstract: OBJECTIVE
  Insulin effects reportedly involve reactive oxygen species (ROS) and oxidative stress in vitro, but skeletal muscle oxidative stress is an emerging negative regulator of insulin action following high-fat feeding. NEFA may enhance oxidative stress and insulin resistance. We investigated the acute impact of insulin with or without NEFA elevation on muscle ROS generation and insulin signalling, and the potential association with altered muscle mitochondrial function.
  
  
  METHODS
  We used hyperinsulinaemic-euglycaemic clamping, 150 min, without or with lipid infusion to modulate plasma NEFA concentration in lean rats.
  
  
  RESULTS
  Insulin and glucose (Ins) infusion selectively enhanced xanthine oxidase-dependent muscle ROS generation. Ins with lipid infusion (Ins+NEFA) lowered whole-body glucose disposal and muscle insulin signalling, and these effects were associated with high muscle mitochondrial ROS generation and activation of the proinflammatory nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) pathway. Antioxidant infusion prevented NEFA-induced systemic insulin resistance and changes in muscle mitochondrial ROS generation, IκB-NFκB pathway and insulin signalling. Changes in insulin sensitivity and signalling were independent of changes in mitochondrial enzyme activity and ATP production, which, in turn, were not impaired by changes in ROS generation under any condition.
  
  
  CONCLUSIONS
  Acute muscle insulin effects include enhanced ROS generation through xanthine oxidase. Additional NEFA elevation enhances mitochondrial ROS generation, activates IκB-NFκB and reduces insulin signalling. These alterations are not associated with acute reductions in mitochondrial enzyme activity and ATP production, and are reversed by antioxidant infusion. Thus, NEFA acutely cause systemic and muscle insulin resistance by enhancing muscle oxidative stress through mitochondrial ROS generation and IκB-NFκB activation.
authors.affiliation: Clinica Medica, Department of Medical, Surgical and Health Sciences, University of Trieste, Ospedale Cattinara, Strada di Fiume 447, Trieste, Italy. barazzon@units.it
authors.forename: R
authors.initials: R
authors.lastname: Barazzoni
authors.forename: M
authors.initials: M
authors.lastname: Zanetti
authors.forename: G
authors.initials: G
authors.lastname: Gortan Cappellari
authors.forename: A
authors.initials: A
authors.lastname: Semolic
authors.forename: M
authors.initials: M
authors.lastname: Boschelle
authors.forename: E
authors.initials: E
authors.lastname: Codarin
authors.forename: A
authors.initials: A
authors.lastname: Pirulli
authors.forename: L
authors.initials: L
authors.lastname: Cattin
authors.forename: G
authors.initials: G
authors.lastname: Guarnieri
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism*; D007262:Infusions, Intravenous; D007333:Insulin Resistance; D061386:Insulin, Regular, Human / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D020672:I-kappa B Proteins; D061386:Insulin, Regular, Human; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014969:Xanthine Oxidase