title: Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease.
abstract: OBJECTIVE
  Alterations in insulin signalling could contribute to insulin resistance in Type II (non-insulin-dependent) diabetes mellitus. Some of these alterations could be secondary to the diabetic state, ie. the hyperglycaemia or increased NEFA concentrations. We sought to exclude such secondary factors and to investigate whether Type II diabetes in itself is associated with altered insulin signalling in skeletal muscle.
  
  
  METHODS
  Hyperinsulinaemic-euglycaemic clamps were performed in 10 obese Type II diabetic patients whose glucose concentrations had been normalised for 8 h by plasma glucose-adapted insulin infusion, 10 BMI-matched first-degree relatives of Type II diabetic patients, and 10 BMI-matched non-diabetic subjects. Muscle biopsies were obtained before and at the end of the clamps, and insulin receptor kinase activity, phosphatidylinositol-3'-kinase activity, Akt-Thr(308)-phosphorylation, and glycogen synthase activity determined.
  
  
  RESULTS
  At similar steady-state clamp insulin concentrations (approximately 400 pmol/l) similar receptor kinase activities, phosphatidylinositol-3'-kinase activities, Akt-Thr(308)-phosphorylation, and glycogen synthase activities were found in all subject groups although glucose disposal was reduced in the diabetic subjects and relatives. Pre-clamp signalling levels were different between subject groups, most likely due to different pre-clamp insulin concentrations.
  
  
  CONCLUSIONS
  Our results in subjects at risk for the development of diabetes and Type II diabetic patients with normalized glucose concentrations suggest that Type II diabetes in itself is not associated with reduced signalling intensity at the studied signalling molecules, at least not at the chosen clamp insulin concentration and under the chosen conditions. Alterations responsible for the reduced glucose disposal could be located downstream of the investigated steps or in alternative insulin signalling pathways. A different spatial organisation of the investigated signalling molecules can also not be excluded.
authors.affiliation: Department of Internal Medicine, Medical University Lübeck, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Meyer
authors.forename: K
authors.initials: K
authors.lastname: Levin
authors.forename: T
authors.initials: T
authors.lastname: Grimmsmann
authors.forename: H
authors.initials: H
authors.lastname: Beck-Nielsen
authors.forename: H H
authors.initials: HH
authors.lastname: Klein
mesh_terms: D000328:Adult; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D004789:Enzyme Activation; D005190:Family; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015309:Glucose Clamp Technique; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D009765:Obesity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D006006:Glycogen Synthase; D019869:Phosphatidylinositol 3-Kinases; C410467:insulin receptor tyrosine kinase; D011505:Protein-Tyrosine Kinases