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

Wolfgang Högler, David D. Martin, Nicola Crabtree, Peter Nightingale, Jeremy Tomlinson, Lou Metherell, Ronald (Ron) Rosenfeld, Vivian Hwa, Stephen Rose, Joanna Walker, Nicholas Shaw, Timothy Barrett, Jan Frystyk

Research output: Contribution to journalArticle

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Abstract

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-g/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting bloodlevels,dual-energyX- rayabsorptiometry,peripheralquantitativecomputedtomography,andmetacarpal 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,andmetacarpal width.Boneanalysisshowedthat 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 comparedwith severe PIGFD, ALS-deficient patients cannotmountasimilar response. Alternativeways of rhIGF-I administration should be sought.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number4
DOIs
StatePublished - 2014

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Pharmacokinetics
Gene Dosage
Bone Development
Body Composition
Insulin-Like Growth Factor I
Metabolism
Bone
Genes
Glucose
Serum
Chemical analysis
Insulin-Like Growth Factor Binding Protein 3
Acids
Insulin Resistance
Insulin
Muscle
Muscles
Metabolic Bone Diseases
Glucose Tolerance Test

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Högler, Wolfgang; Martin, David D.; Crabtree, Nicola; Nightingale, Peter; Tomlinson, Jeremy; Metherell, Lou; Rosenfeld, Ronald (Ron); Hwa, Vivian; Rose, Stephen; Walker, Joanna; Shaw, Nicholas; Barrett, Timothy; Frystyk, Jan.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 4, 2014.

Research output: Contribution to journalArticle

Högler, W, Martin, DD, Crabtree, N, Nightingale, P, Tomlinson, J, Metherell, L, Rosenfeld, RR, Hwa, V, Rose, S, Walker, J, Shaw, N, Barrett, T & Frystyk, J 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', Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 4. https://doi.org/10.1210/jc.2013-3718
Högler, Wolfgang ; Martin, David D. ; Crabtree, Nicola ; Nightingale, Peter ; Tomlinson, Jeremy ; Metherell, Lou ; Rosenfeld, Ronald (Ron) ; Hwa, Vivian ; Rose, Stephen ; Walker, Joanna ; Shaw, Nicholas ; Barrett, Timothy ; Frystyk, Jan. / 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. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 4.
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abstract = "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-g/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting bloodlevels,dual-energyX- rayabsorptiometry,peripheralquantitativecomputedtomography,andmetacarpal 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,andmetacarpal width.Boneanalysisshowedthat 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 comparedwith severe PIGFD, ALS-deficient patients cannotmountasimilar response. Alternativeways of rhIGF-I administration should be sought.",
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T1 - 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

AU - Högler, Wolfgang

AU - Martin, David D.

AU - Crabtree, Nicola

AU - Nightingale, Peter

AU - Tomlinson, Jeremy

AU - Metherell, Lou

AU - Rosenfeld, Ronald (Ron)

AU - Hwa, Vivian

AU - Rose, Stephen

AU - Walker, Joanna

AU - Shaw, Nicholas

AU - Barrett, Timothy

AU - Frystyk, Jan

PY - 2014

Y1 - 2014

N2 - 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-g/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting bloodlevels,dual-energyX- rayabsorptiometry,peripheralquantitativecomputedtomography,andmetacarpal 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,andmetacarpal width.Boneanalysisshowedthat 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 comparedwith severe PIGFD, ALS-deficient patients cannotmountasimilar response. Alternativeways of rhIGF-I administration should be sought.

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-g/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting bloodlevels,dual-energyX- rayabsorptiometry,peripheralquantitativecomputedtomography,andmetacarpal 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,andmetacarpal width.Boneanalysisshowedthat 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 comparedwith severe PIGFD, ALS-deficient patients cannotmountasimilar response. Alternativeways of rhIGF-I administration should be sought.

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