ALS deficiency: insulin resistance, bone strength & response to rhIGF1

• Research type

  Research Study

• Full title

  A pharmacokinetic and pharmacodynamic study of recombinant human IGF-I (rhIGF-I) in three boys with ALS deficiency, and insulin sensitivity and bone density in patients and heterozygous first-degree relatives.

• IRAS ID

  32016

• Contact name

  Dozent Dr Wolfgang Hogler

• Sponsor organisation

  Queen Elizabeth Hospital

• Eudract number

  2010-019296-30

• ISRCTN Number

  N/A

• Research summary

  Growth hormone (GH) and insulin-like growth factor (IGF-I) are essential for normal growth, bone health, maintenance of body composition and blood sugar homeostasis. GH causes formation of IGF-I in the liver, which is transported to its sites of action bound to acid labile subunit (ALS) and specific binding proteins (IGFBPs). The most prevalent is a ternary complex, consisting of IGF-I bound to IGFBP-3 and ALS, which prolongs IGF-1??s half-life. Primary IGF-1 deficiency is a heterogeneous group of conditions with normal GH secretion but impaired IGF-1 production or action, causing short stature. Treatment with recombinant IGF-1 (rhIGF-I) is indicated and licensed for primary IGF-1 deficiency. One of these disorders is ALS deficiency, an extremely rare condition where affected patients lack ALS and are therefore unable to form ternary complexes, causing rapid clearance of IGF-1 and growth failure. This study will provide important information whether three (of 17 worldwide) ALS deficient patients with an IGFALS gene mutation can actually respond to a rhIGF-I injection. Information gathered on free (unbound to ALS) and total IGF-1 for 14 hours after a single injection will help us understand the pharmacokinetics & pharmacodynamics of IGF-I in these patients, and will assist in designing and optimizing treatment dosing regimens for these patients. In addition, there is preliminary evidence suggesting that insulin sensitivity and bone strength could be compromised in ALS deficient patients and heterozygote carriers, potentially exposing them to an increased risk of diabetes or osteoporosis. This study will investigate glucose homeostasis using intravenous glucose tolerance tests and bone strength using peripheral quantitative computer tomography and dual-energy x-ray absorptiometry in the patients and their first-degree relatives. The information gained in relation to homo/heterozygocity for IGFALS gene mutations will help guiding clinicians in the long-term follow-up of patients with this extremely rare condition.

• REC name

  West Midlands - Edgbaston Research Ethics Committee

• REC reference

  10/H1208/25

• Date of REC Opinion

  18 May 2010

• REC opinion

  Further Information Favourable Opinion