title: Increased mitochondrial substrate sensitivity in skeletal muscle of patients with type 2 diabetes.
abstract: OBJECTIVE
  Mitochondrial respiration has been linked to insulin resistance. We studied mitochondrial respiratory capacity and substrate sensitivity in patients with type 2 diabetes (patients), and obese and lean control participants.
  
  
  METHODS
  Mitochondrial respiration was measured in permeabilised muscle fibres by respirometry. Protocols for respirometry included titration of substrates for complex I (glutamate), complex II (succinate) and both (octanoyl-carnitine). Myosin heavy chain (MHC) composition, antioxidant capacity (manganese superoxide dismutase [MnSOD]), citrate synthase activity and maximal oxygen uptake (VO2) were also determined. Insulin sensitivity was determined with the isoglycaemic-hyperinsulinaemic clamp technique.
  
  
  RESULTS
  Insulin sensitivity was different (p < 0.05) between the groups (patients<obese controls<lean controls). MnSOD was lower in patients than in lean controls. MHC I content was lowest in patients (37 ± 11% [mean ± SE] vs 53 ± 6% and 56 ± 4%) vs obese controls and lean controls, respectively. VO2 was highest in lean controls (40 ± 3 ml min(-1) kg(-1) [mean ± SE]) compared with patients (25 ± 2) and obese controls (27 ± 2). Mitochondrial content (citrate synthase) was higher (p < 0.05) in lean controls than in patients and obese controls. When normalised for mitochondrial content by citrate synthase, mitochondrial respiratory capacity was similar in all groups. However, the half maximal substrate concentration (C(50)) for complex I was significantly lower (p = 0.03) in patients (1.1 ± 0.2 mmol/l [mean ± SE]) than in obese (2.0 ± 0.3) and lean (1.8 ± 0.3) controls. Likewise, C(50) for complex II was lower (p = 0.02) in patients (3.5 ± 0.2 mmol/l [mean ± SE]) than in obese controls (4.1 ± 0.2), but did not differ from that in lean controls (3.8 ± 0.4). Substrate sensitivity for octanoyl-carnitine did not differ between groups.
  
  
  CONCLUSIONS
  Increased mitochondrial substrate sensitivity is seen in skeletal muscle from type 2 diabetic patients and is confined to non-lipid substrates. Respiratory capacity per mitochondrion is not decreased with insulin resistance.
authors.affiliation: Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health Sciences, Copenhagen University, Blegdamsvej 3b, 2200 Copenhagen N, Denmark. stelar@sund.ku.dk
authors.forename: S
authors.initials: S
authors.lastname: Larsen
authors.forename: N
authors.initials: N
authors.lastname: Stride
authors.forename: M
authors.initials: M
authors.lastname: Hey-Mogensen
authors.forename: C N
authors.initials: CN
authors.lastname: Hansen
authors.forename: J L
authors.initials: JL
authors.lastname: Andersen
authors.forename: S
authors.initials: S
authors.lastname: Madsbad
authors.forename: D
authors.initials: D
authors.lastname: Worm
authors.forename: J W
authors.initials: JW
authors.lastname: Helge
authors.forename: F
authors.initials: F
authors.lastname: Dela
mesh_terms: D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D016022:Case-Control Studies; D019069:Cell Respiration / Q000502:physiology; D002950:Citrate (si)-Synthase / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity; D019802:Succinic Acid / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013851:Thinness / Q000378:metabolism / Q000473:pathology
chemical_list: D018698:Glutamic Acid; D019802:Succinic Acid; D013482:Superoxide Dismutase; D002950:Citrate (si)-Synthase; D018995:Myosin Heavy Chains; C008698:octanoylcarnitine; D002331:Carnitine