Ten-year improvement of insulin resistance and growth with recombinant human insulin-like growth factor 1 in a patient with insulin receptor mutations resulting in leprechaunism

M de Kerdanet; M Caron-Debarle; S Nivot; T Gaillot; O Lascols; B Fremont; M Bonaure; S Gie; C Massart; J Capeau

doi:10.1016/j.diabet.2014.11.001

Ten-year improvement of insulin resistance and growth with recombinant human insulin-like growth factor 1 in a patient with insulin receptor mutations resulting in leprechaunism

Diabetes Metab. 2015 Sep;41(4):331-337. doi: 10.1016/j.diabet.2014.11.001. Epub 2014 Nov 25.

Authors

M de Kerdanet¹, M Caron-Debarle², S Nivot³, T Gaillot³, O Lascols², B Fremont⁴, M Bonaure³, S Gie³, C Massart⁵, J Capeau²

Affiliations

¹ Pediatric Endocrinology Unit, University Hospital, Rennes, France. Electronic address: marc.de.kerdanet@chu-rennes.fr.
² INSERM, UMR-S 938, CDR Saint-Antoine, 75012 Paris, France; Sorbonne University UPMC Université Paris 06, UMR-S 938, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), AP-HP, GH HUEP, 75012 Paris, France.
³ Pediatric Endocrinology Unit, University Hospital, Rennes, France.
⁴ Pediatric surgery service, University Hospital, Rennes, France.
⁵ Laboratory of Molecular Genetic and Hormonology, University Hospital, Rennes, France.

PMID: 25465274
DOI: 10.1016/j.diabet.2014.11.001

Abstract

Aim: Leprechaunism, a rare genetic disease resulting from mutations in two alleles of the insulin receptor gene, is characterized by severe insulin resistance, retarded growth and, usually, premature death. The ability of treatment with recombinant human insulin-like growth factor 1 (rhIGF1) to improve metabolic and clinical parameters in the long-term is still controversial.

Methods: Mutations were looked for in the insulin receptor gene of a four-month-old female baby with leprechaunism. The patient's skin fibroblasts were analyzed for response to insulin and IGF1. At the clinical level, the very long-term effects of treatment with rhIGF1/rhIGFBP3 were evaluated by clinical and metabolic parameters.

Results: The patient's diagnosis was based on compound heterozygous mutations in two alleles of the insulin receptor gene, thus confirming leprechaunism. Cultured fibroblasts showed a decreased number of insulin receptors and were insulin-resistant. However, IGF1 was able to stimulate IGF1 receptor signalling, suggesting possible activation of a salvage pathway. Treatment with IGF1/IGFBP3 for 8.7 years, then IGF1 for 2 years, resulted in normalization of circulating levels of IGF1 and IGFBP3. Large daily variations in glycaemia and insulinaemia persisted, but mean glycaemia decreased. Regarding growth, the patient's BMI Z score normalized and length/height score improved. Our patient presented normal neurological development and academic achievement. The treatment was free of adverse effects.

Conclusion: Our results provide evidence that rhIGF1 with and without rhIGFBP3 can prevent fatal outcomes, and improve growth and metabolic parameters, for more than 10 years in a patient with leprechaunism. Long-term rhIGF1 for severe insulin resistance syndrome should be considered.

Keywords: Insulin resistance; Leprechaunism; rhIGF1; rhIGFBP3.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Antigens, CD / genetics*
Child
Child Development* / drug effects
Child, Preschool
Donohue Syndrome / drug therapy*
Donohue Syndrome / genetics
Donohue Syndrome / metabolism
Donohue Syndrome / physiopathology
Female
Follow-Up Studies
Hormone Replacement Therapy
Humans
Infant
Insulin Resistance / genetics*
Insulin-Like Growth Factor I / metabolism
Insulin-Like Growth Factor I / therapeutic use*
Mutation*
Receptor, Insulin / genetics*
Recombinant Proteins / therapeutic use
Treatment Outcome

Substances

Antigens, CD
Recombinant Proteins
Insulin-Like Growth Factor I
INSR protein, human
Receptor, Insulin