title: Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes.
abstract: BACKGROUND
  Muscular insulin resistance is frequently characterized by blunted increases in glucose-6-phosphate (G-6-P) reflecting impaired glucose transport/phosphorylation. These abnormalities likely relate to excessive intramyocellular lipids and mitochondrial dysfunction. We hypothesized that alterations in insulin action and mitochondrial function should be present even in nonobese patients with well-controlled type 2 diabetes mellitus (T2DM).
  
  
  RESULTS
  We measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with (31)P/(1)H magnetic resonance spectroscopy in ten patients with T2DM and in two control groups: ten sex-, age-, and body mass-matched elderly people; and 11 younger healthy individuals. Although insulin sensitivity was lower in patients with T2DM, muscle lipid contents were comparable and hyperinsulinemia increased G-6-P by 50% (95% confidence interval [CI] 39%-99%) in all groups. Patients with diabetes had 27% lower fasting ATP synthetic flux compared to younger controls (p = 0.031). Insulin stimulation increased ATP synthetic flux only in controls (younger: 26%, 95% CI 13%-42%; older: 11%, 95% CI 2%-25%), but failed to increase even during hyperglycemic hyperinsulinemia in patients with T2DM. Fasting free fatty acids and waist-to-hip ratios explained 44% of basal ATP synthetic flux. Insulin sensitivity explained 30% of insulin-stimulated ATP synthetic flux.
  
  
  CONCLUSIONS
  Patients with well-controlled T2DM feature slightly lower flux through muscle ATP synthesis, which occurs independently of glucose transport /phosphorylation and lipid deposition but is determined by lipid availability and insulin sensitivity. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities mainly in glycogen synthesis in these patients.
authors.affiliation: Department of Internal Medicine 3, University of Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Szendroedi
authors.forename: Albrecht I
authors.initials: AI
authors.lastname: Schmid
authors.forename: Marek
authors.initials: M
authors.lastname: Chmelik
authors.forename: Christian
authors.initials: C
authors.lastname: Toth
authors.forename: Attila
authors.initials: A
authors.lastname: Brehm
authors.forename: Martin
authors.initials: M
authors.lastname: Krssak
authors.forename: Peter
authors.initials: P
authors.lastname: Nowotny
authors.forename: Michael
authors.initials: M
authors.lastname: Wolzt
authors.forename: Werner
authors.initials: W
authors.lastname: Waldhausl
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000273:Adipose Tissue / Q000378:metabolism / Q000502:physiology; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D015309:Glucose Clamp Technique; D019298:Glucose-6-Phosphate / Q000097:blood; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D019298:Glucose-6-Phosphate; D000255:Adenosine Triphosphate