title: IGFALS gene dosage effects on serum IGF-I and glucose metabolism, body composition, bone growth in length and width, and the pharmacokinetics of recombinant human IGF-I administration.
abstract: BACKGROUND
  Acid labile subunit (ALS) deficiency, caused by IGFALS mutations, is a subtype of primary IGF-I deficiency (PIGFD) and has been associated with insulin resistance (IR) and osteopenia. Whether patients respond to recombinant human IGF-I (rhIGF-I) is unknown.
  
  
  OBJECTIVE
  This study determined the 14-hour pharmacokinetic response of free and total IGF-I and IGF binding protein 3 (IGFBP-3) to a single sc dose of rhIGF-I (120 μg/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting blood levels, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and metacarpal radiogrammetry were performed in the four patients and 12 heterozygous family members.
  
  
  RESULTS
  IGF-I and IGFBP-3 increased above baseline (P < .05) for 2.5 hours, returning to baseline 7 hours after rhIGF-I injection. Mean (SD) IGF-I Z-score increased by 2.49 (0.90), whereas IGFBP-3 Z-score increased by 0.57 (0.10) only. IGF-I elimination rates in ALS deficiency were similar, but the IGF-I increment was lower than those for severe PIGFD. Significant gene dosage effects were found for all IGF-I peptides, height, forearm muscle size, and metacarpal width. Bone analysis showed that ALS deficiency creates a phenotype of slender bones with normal size-corrected density. Abnormal glucose handling and IR was found in three of four patients and 6 of 12 carriers.
  
  
  CONCLUSIONS
  These gene dosage effects demonstrate that one functional IGFALS allele is insufficient to maintain normal ALS levels, endocrine IGF-I action, full growth potential, muscle size, and periosteal expansion. Similar gene dosage effects may exist for parameters of IR. Despite similar IGF-I elimination compared with severe PIGFD, ALS-deficient patients cannot mount a similar response. Alternative ways of rhIGF-I administration should be sought.
authors.affiliation: Departments of Endocrinology and Diabetes (W.H., N.S., T.B.) and Nuclear Medicine (N.C.), Birmingham Children's Hospital, B4 6NH Birmingham, United Kingdom; Department of Paediatric Endocrinology and Diabetes (D.D.M.), University Children's Hospital, D-72074 Tübingen, Germany; Wellcome Trust Clinical Research Facility (P.N.), Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom; School of Clinical and Experimental Medicine (J.T., T.B.), University of Birmingham, Birmingham B15 2TT, United Kingdom; William Harvey Research Institute (L.M.), Barts and the London School of Medicine, Queen Mary University of London, London E1 1BB, United Kingdom; Department of Paediatrics (R.R.), Oregon Health Sciences University, Portland, Oregon 97239; Department of Paediatrics (S.R.), Heartlands Hospital, B9 5SS Birmingham, United Kingdom; Department of Paediatrics (J.W.), Portsmouth Hospital, Portsmouth PO6 3LY, United Kingdom; and Medical Research Laboratory (J.F.), Department of Clinical Medicine, Faculty of Health, Aarhus University, and Department of Endocrinology and Internal Medicine, Aarhus University Hospital, DK-8000 C Aarhus, Denmark.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Högler
authors.forename: David D
authors.initials: DD
authors.lastname: Martin
authors.forename: Nicola
authors.initials: N
authors.lastname: Crabtree
authors.forename: Peter
authors.initials: P
authors.lastname: Nightingale
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tomlinson
authors.forename: Lou
authors.initials: L
authors.lastname: Metherell
authors.forename: Ron
authors.initials: R
authors.lastname: Rosenfeld
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Stephen
authors.initials: S
authors.lastname: Rose
authors.forename: Joanna
authors.initials: J
authors.lastname: Walker
authors.forename: Nicholas
authors.initials: N
authors.lastname: Shaw
authors.forename: Timothy
authors.initials: T
authors.lastname: Barrett
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D001823:Body Composition / Q000235:genetics*; D015519:Bone Density; D001846:Bone Development / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D018628:Gene Dosage / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D006023:Glycoproteins; D011994:Recombinant Proteins; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I