title: Ascorbic acid supplementation improves skeletal muscle oxidative stress and insulin sensitivity in people with type 2 diabetes: Findings of a randomized controlled study.
abstract: OBJECTIVE
  Skeletal muscle insulin resistance and oxidative stress are characteristic metabolic disturbances in people with type 2 diabetes. Studies in insulin resistant rodents show an improvement in skeletal muscle insulin sensitivity and oxidative stress following antioxidant supplementation. We therefore investigated the potential ameliorative effects of antioxidant ascorbic acid (AA) supplementation on skeletal muscle insulin sensitivity and oxidative stress in people with type 2 diabetes.
  
  
  METHODS
  Participants with stable glucose control commenced a randomized cross-over study involving four months of AA (2 × 500 mg/day) or placebo supplementation. Insulin sensitivity was assessed using a hyperinsulinaemic, euglycaemic clamp coupled with infusion of 6,6-D2 glucose. Muscle biopsies were measured for AA concentration and oxidative stress markers that included basal measures (2',7'-dichlorofluorescin [DCFH] oxidation, ratio of reduced-to-oxidized glutathione [GSH/GSSG] and F2-Isoprostanes) and insulin-stimulated measures (DCFH oxidation). Antioxidant concentrations, citrate synthase activity and protein abundances of sodium-dependent vitamin C transporter 2 (SVCT2), total Akt and phosphorylated Akt (ser473) were also measured in muscle samples.
  
  
  RESULTS
  AA supplementation significantly increased insulin-mediated glucose disposal (delta rate of glucose disappearance; ∆Rd) (p=0.009), peripheral insulin-sensitivity index (p=0.046), skeletal muscle AA concentration (p=0.017) and muscle SVCT2 protein expression (p=0.008); but significantly decreased skeletal muscle DCFH oxidation during hyperinsulinaemia (p=0.007) when compared with placebo. Total superoxide dismutase activity was also lower following AA supplementation when compared with placebo (p=0.006). Basal oxidative stress markers, citrate synthase activity, endogenous glucose production, HbA1C and muscle Akt expression were not significantly altered by AA supplementation.
  
  
  CONCLUSIONS
  In summary, oral AA supplementation ameliorates skeletal muscle oxidative stress during hyperinsulinaemia and improves insulin-mediated glucose disposal in people with type 2 diabetes. Findings implicate AA supplementation as a potentially inexpensive, convenient, and effective adjunct therapy in the treatment of insulin resistance in people with type 2 diabetes.
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia.
authors.forename: Shaun A
authors.initials: SA
authors.lastname: Mason
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Della Gatta
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia.
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Snow
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.affiliation: Centre for Physical Activity and Nutrition (C-PAN) Research, School of Exercise and Nutrition Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia. Electronic address: glenn.wadley@deakin.edu.au.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Wadley
mesh_terms: D000368:Aged; D001205:Ascorbic Acid / Q000008:administration & dosage* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D007328:Insulin; D005947:Glucose; D001205:Ascorbic Acid
keywords: Ascorbic acid; Oxidative stress; Skeletal muscle; Type 2 diabetes