Högler, Wolfgang and Martin, David D and Crabtree, Nicola and Nightingale, Peter and Tomlinson, Jeremy and Metherell, Lou and Rosenfeld, Ron and Hwa, Vivian and Rose, Stephen and Walker, Joanna and Shaw, Nicholas and Barrett, Timothy and Frystyk, Jan (2014) 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. The Journal of clinical endocrinology and metabolism, 99 (4). E703-12. ISSN 1945-7197. This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their Athens login IDsFull text not available from this repository.
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 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.
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.
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.
|Additional Information:||This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their Athens login IDs|
|Subjects:||WK Endocrine system. Endocrinology|
|Divisions:||Womens and Childrens > Paediatrics|
|Depositing User:||Mrs Yolande Brookes|
|Date Deposited:||18 Aug 2014 14:48|
|Last Modified:||18 Aug 2014 14:48|
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