title: Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes.
abstract: OBJECTIVE
  in type 2 diabetic patients and their first-degree relatives, insulin resistance (IR) is associated with impairment of insulin-stimulated myocellular glucose-6-phosphate (g6p) and unidirectional flux through ATP synthase (fATP), suggesting the presence of inherited abnormal mitochondrial oxidative fitness. We hypothesized that patients with long-standing type 1 diabetes may also exhibit insulin resistance as well as lower fATP.
  
  
  METHODS
  this single-centre trial was registered at ClinicalTrials.gov (NCT00481598).
  
  
  METHODS
  we included eight nonobese type 1 diabetic patients (mean diabetes duration: 17 years) with near-target glycaemic control [haemoglobin A1c (HbA1c): 6.8 ± 0.4%] during treatment with continuous subcutaneous insulin infusion pumps and eight healthy volunteers (HbA1c: 5.4 ± 0.2%) of comparable age, body mass and level of physical activity.
  
  
  METHODS
  myocellular fATP, g6p and intramyocellular lipid content (IMCL) were measured with (1) H/(31) P magnetic resonance spectroscopy during fasting and hyperinsulinaemic-euglycaemic clamp tests.
  
  
  RESULTS
  fasting fATP, g6p and IMCL did not differ between groups. During stimulation by insulin, type 1 diabetic patients exhibited approximately 50% (P < 0.001) lower whole-body glucose disposal along with approximately 42% (P = 0.003) lower intramyocellular g6p and approximately25% (P = 0.024) lower fATP. Insulin-stimulated fATP correlated positively with whole-body insulin sensitivity (R = 0.706, P = 0.002) and negatively with HbA1c (R = -0.675, P = 0.004).
  
  
  CONCLUSIONS
  despite documented near-target glycaemic control for 1 year, nonobese patients with long-standing type 1 diabetes can exhibit insulin resistance. This associates with lower insulin-stimulated flux through muscular ATP synthase which could result from glucose toxicity.
authors.affiliation: Karl-Landsteiner Institute for Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Kacerovsky
authors.forename: A
authors.initials: A
authors.lastname: Brehm
authors.forename: M
authors.initials: M
authors.lastname: Chmelik
authors.forename: A I
authors.initials: AI
authors.lastname: Schmid
authors.forename: J
authors.initials: J
authors.lastname: Szendroedi
authors.forename: G
authors.initials: G
authors.lastname: Kacerovsky-Bielesz
authors.forename: P
authors.initials: P
authors.lastname: Nowotny
authors.forename: A
authors.initials: A
authors.lastname: Lettner
authors.forename: M
authors.initials: M
authors.lastname: Wolzt
authors.forename: J G
authors.initials: JG
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: Roden
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000328:Adult; D000886:Anthropometry / Q000379:methods; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D005215:Fasting / Q000502:physiology; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D055104:Infusions, Subcutaneous; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D000255:Adenosine Triphosphate