PMID- 24423360
OWN - NLM
STAT- MEDLINE
DCOM- 20140603
LR  - 20220302
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Linking)
VI  - 99
IP  - 4
DP  - 2014 Apr
TI  - 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.
PG  - E703-12
LID - 10.1210/jc.2013-3718 [doi]
AB  - CONTEXT: 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 AND DESIGN: 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 mug/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.
FAU - Hogler, Wolfgang
AU  - Hogler W
AD  - 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 Tubingen, 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.
FAU - Martin, David D
AU  - Martin DD
FAU - Crabtree, Nicola
AU  - Crabtree N
FAU - Nightingale, Peter
AU  - Nightingale P
FAU - Tomlinson, Jeremy
AU  - Tomlinson J
FAU - Metherell, Lou
AU  - Metherell L
FAU - Rosenfeld, Ron
AU  - Rosenfeld R
FAU - Hwa, Vivian
AU  - Hwa V
FAU - Rose, Stephen
AU  - Rose S
FAU - Walker, Joanna
AU  - Walker J
FAU - Shaw, Nicholas
AU  - Shaw N
FAU - Barrett, Timothy
AU  - Barrett T
FAU - Frystyk, Jan
AU  - Frystyk J
LA  - eng
GR  - G0801265/MRC_/Medical Research Council/United Kingdom
GR  - MR/K020455/1/MRC_/Medical Research Council/United Kingdom
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140113
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Blood Glucose)
RN  - 0 (Carrier Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (insulin-like growth factor binding protein, acid labile subunit)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
SB  - IM
MH  - Adult
MH  - Blood Glucose/*metabolism
MH  - Body Composition/*genetics
MH  - Bone Density
MH  - Bone Development/*genetics
MH  - Carrier Proteins/*genetics
MH  - Child
MH  - Child, Preschool
MH  - Cross-Sectional Studies
MH  - Gene Dosage/*physiology
MH  - Glycoproteins/*genetics
MH  - Humans
MH  - Insulin-Like Growth Factor I/administration & dosage/*metabolism/pharmacokinetics
MH  - Middle Aged
MH  - Recombinant Proteins/administration & dosage/pharmacokinetics
MH  - Young Adult
EDAT- 2014/01/16 06:00
MHDA- 2014/06/04 06:00
CRDT- 2014/01/16 06:00
PHST- 2014/01/16 06:00 [entrez]
PHST- 2014/01/16 06:00 [pubmed]
PHST- 2014/06/04 06:00 [medline]
AID - 10.1210/jc.2013-3718 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2014 Apr;99(4):E703-12. doi: 10.1210/jc.2013-3718. Epub 
      2014 Jan 13.