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; Crabtree, Nicola; Tomlinson, Jeremy W.; Metherell, Louise A.; Rosenfeld, Ron G.; Hwa, Vivian; Rose, Stephen; Walker, Judith S.; Shaw, Nicholas; Barrett, Timothy; Frystyk, Jan

doi:10.1210/jc.2013-3718

Cited by 26 publications

(18 citation statements)

References 51 publications

(58 reference statements)

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“…Lack of ternary complex formation due to ALS deletion was associated with increased adipogenesis from bone marrowderived mesenchymal stromal cells in culture, whereas recombinant ALS inhibited adipogenesis (43). Although ALS-deficient mice had normal body composition and insulin sensitivity (45), humans with ALS deficits are insulinresistant (46,47) and may be obese (47). Therefore, the lack of ternary complex formation of the mutant hIGFBP-3 could explain adiposity and insulin resistance in PGKmutBP3 mice.…”

Section: Discussionmentioning

confidence: 99%

Glucose Intolerance in Aging Male IGFBP-3 Transgenic Mice: Differential Effects of Human IGFBP-3 and Its Mutant IGFBP-3 Devoid of IGF Binding Ability

et al. 2014

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We have reported a reduction of insulin secretion and glucose intolerance in young mice overexpressing human IGFBP-3 (phosphoglycerate kinase [PGK]BP3) or its mutant Gly56/Gly80/Gly81-IGFBP-3 (PGKmutBP3) under the PGK promoter. Here, we investigated changes in glucose and lipid homeostasis with age in PGKBP3 and PGKmutBP3 mice compared with wild-type mice. Body weight, glucose tolerance, insulin tolerance, visceral fat, interscapular brown adipose tissue (BAT), serum lipids, and pancreas histology were examined at age 3, 6, and 12 months. Murine IGFBP-3 was similar in all mouse genotypes and decreased with age in parallel with total IGF-1. Visceral fat and BAT masses increased in PGKmutBP3 mice, but not in PGKBP3 mice. Glucose tolerance was impaired in both PGKBP3 and PGKmutBP3 mice. However, PGKBP3 mice had increased expression of uncoupling protein-1 in BAT and reduced adiposity, and continued to have smaller pancreatic β-cell mass and reduced insulin secretion through age 12 months. In contrast, PGKmutBP3 mice developed insulin resistance with age in association with pancreatic β-cell hyperplasia, impaired expression of uncoupling protein-1 in BAT, and increased adiposity. In addition, both PGKBP3 and PGKmutBP3 mice had elevated glycerol in the circulation, but only PGKBP3 mice had elevated free fatty acids and only PGKmutBP3 mice had elevated triglycerides. Estimated free IGF-1 did not increase with age in transgenic mice, as it did in wild-type mice. Thus, overexpression of human IGFBP-3 or its mutant devoid of IGF binding ability leads to glucose intolerance with, however, different effects on insulin secretion, insulin sensitivity, and lipid homeostasis in aging mice.

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Section: Discussionmentioning

confidence: 99%

Glucose Intolerance in Aging Male IGFBP-3 Transgenic Mice: Differential Effects of Human IGFBP-3 and Its Mutant IGFBP-3 Devoid of IGF Binding Ability

et al. 2014

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“…Patients with IGFALS defects do not respond well to either GH or IGF-I treatment. Despite profoundly low circulating concentrations of IGF-I, their growth failure is mild [241,242] . Technical Remark: Outside of the USA, IGF-I is also used at 150-180 μg/kg once daily.…”

Section: Gh Treatment Of Patients With Issmentioning

confidence: 99%

Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency

DiVall²,

et al. 2016

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Background/Aims: On behalf of the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society, we sought to update the guidelines published in 2003 on the use of growth hormone (GH). Because idiopathic short stature (ISS) remains a controversial indication, and diagnostic challenges often blur the distinction between ISS, GH deficiency (GHD), and primary IGF-I deficiency (PIGFD), we focused on these three diagnoses, thereby adding recombinant IGF-I therapy to the GH guidelines for the first time. Methods: This guideline was developed following the GRADE approach (Grading of Recommendations, Assessment, Development, and Evaluation). Results: This guideline provides recommendations for the clinical management of children and adolescents with growth failure from GHD, ISS, or PIGFD using the best available evidence. Conclusion: The taskforce suggests that the recommendations be applied in clinical practice with consideration of the evolving literature and the risks and benefits to each individual patient. In many instances, careful review highlights areas that need further research.

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“…Children with ALS deficiency show a mild growth failure, delayed puberty, undetectable serum ALS, low serum IGF1, and even lower IGF binding protein 3 (IGFBP-3) (59), and variable osteopenia and hyperinsulinism (60,61,62). Heterozygosity for IGFALS variants causes a one S.D.…”

Section: Gh Deficiencymentioning

confidence: 99%

“…Heterozygosity for IGFALS variants causes a one S.D. lower height (60,62,63) and may be responsible for a subset of children previously considered having ISS (64).…”

Section: Gh Deficiencymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

141

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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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

Cited by 26 publications

References 51 publications

Glucose Intolerance in Aging Male IGFBP-3 Transgenic Mice: Differential Effects of Human IGFBP-3 and Its Mutant IGFBP-3 Devoid of IGF Binding Ability

Glucose Intolerance in Aging Male IGFBP-3 Transgenic Mice: Differential Effects of Human IGFBP-3 and Its Mutant IGFBP-3 Devoid of IGF Binding Ability

Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

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