title: Anabolic resistance does not explain sarcopenia in patients with type 2 diabetes mellitus, compared with healthy controls, despite reduced mTOR pathway activity.
abstract: Ageing and type 2 diabetes mellitus (T2DM) are risk factors for skeletal muscle loss. We investigated whether anabolic resistance to feeding might underlie accelerated muscle loss in older people with T2DM and whether dysregulated mTOR signalling was implicated.
  
  
  
  8 obese men with T2DM, and 12 age-matched controls were studied (age 68 ± 3 vs. 68±6 y; BMI: 30 ± 2 vs. 27 ± 5 kg m-2).
  
  
  
  Body composition was measured by dual-X-ray absorptiometry. Insulin and glucose were clamped at post-absorptive concentrations (13 ± 2 vs. 9 ± 3 mU l-1; 7.4 ± 1.9 vs. 4.6 ± 0.4 mmol l-1; T2DM vs. controls). Fractional synthetic rates (FSR) of myofibrillar and sarcoplasmic proteins were measured as the rate of incorporation of [13C] leucine during a primed, constant infusion of [1-13C] α-ketoisocaproic acid, 3 h after 10 or 20 g of essential amino acids (EAA) were orally administered. Protein expression of total and phosphorylated mTOR signalling proteins was determined by Western blot analysis.
  
  
  
  Despite a significantly lower appendicular lean mass index and a greater fat mass index in T2DM vs. controls, basal myofibrillar and sarcoplasmic and post-prandial myofibrillar FSR were similar. After 20 g EAA, stimulation of sarcoplasmic FSR was slightly blunted in T2DM patients. Furthermore, feeding 20 g EAA increased phosphorylation of mTOR, p70S6kand 4E-BP1 by 60-100% in controls with no response observed in T2DM.
  
  
  
  There was clear dissociation between changes in mTOR signalling versus changes in protein synthesis rates. However, the intact anabolic response of myofibrillar FSR to feeding in both groups suggests anabolic resistance may not explain accelerated muscle loss in T2DM.
authors.affiliation: Medical Research Council-Arthritis UK Centre of Excellence for Musculoskeletal Ageing Research, University of Liverpool, L69 3GA, UK. Electronic address: daniel.cuthbertson@liverpool.ac.uk.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cuthbertson
authors.affiliation: University of Abertay, Dundee, Scotland, UK.
authors.forename: John
authors.initials: J
authors.lastname: Babraj
authors.affiliation: Department of Diabetes, Ninewells Hospital and Medical School, Dundee, Scotland, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Leese
authors.affiliation: Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle on Tyne, NE4 5PL, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Siervo
mesh_terms: D015502:Absorptiometry, Photon; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000601:Amino Acids, Essential / Q000008:administration & dosage / Q000097:blood; D045930:Anabolic Agents / Q000008:administration & dosage* / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D015992:Body Mass Index; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications*; D006801:Humans; D007328:Insulin / Q000097:blood; D007651:Keto Acids / Q000008:administration & dosage / Q000097:blood; D007930:Leucine / Q000008:administration & dosage / Q000097:blood; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D019518:Postprandial Period; D014176:Protein Biosynthesis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D055948:Sarcopenia / Q000097:blood / Q000209:etiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000601:Amino Acids, Essential; D045930:Anabolic Agents; D001786:Blood Glucose; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007328:Insulin; D007651:Keto Acids; D009124:Muscle Proteins; D010750:Phosphoproteins; C013082:alpha-ketoisocaproic acid; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D007930:Leucine
keywords: Anabolic resistance; Insulin resistance; Obesity; Protein synthesis; Sarcopenia; Skeletal muscle