Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase.
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Authors
Leiter, Sarah M
Parker, Victoria ER
Welters, Alena
Knox, Rachel
Rocha, Nuno
Clark, Graeme
Harris, Julie
Guerrero-Fernández, Julio
González-Casado, Isabel
García-Miñaur, Sixto
Gordo, Gema
Allison, Michael
Meissner, Thomas
Davies, Susan
Hussain, Khalid
Barreda-Bonis, Ana-Coral
Kummer, Sebastian
Publication Date
2017-08Journal Title
European journal of endocrinology
ISSN
0804-4643
Volume
177
Issue
2
Pages
175-186
Language
English
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Leiter, S. M., Parker, V. E., Welters, A., Knox, R., Rocha, N., Clark, G., Payne, F., et al. (2017). Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase.. European journal of endocrinology, 177 (2), 175-186. https://doi.org/10.1530/eje-17-0132
Abstract
OBJECTIVE: Genetic activation of the insulin signal-transducing kinase AKT2 causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction. METHODS: Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no AKT2 mutation underwent further genetic, clinical, and metabolic investigation. Signalling in dermal fibroblasts from one patient, and efficacy of the mTOR inhibitor Sirolimus on pathway activation was examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was further assessed. RESULTS: In the first three patients mosaic mutations in PIK3CA (p.Gly118Asp or p.Glu726Lys) or PIK3R2 (p.Gly373Arg) were found.. In different tissue samples available from one patient, the PIK3CA p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in PIK3CA had neither clinical nor biochemical evidence of hypoglycaemia. CONCLUSIONS: Mosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy.
Keywords
Humans, Hypoglycemia, Insulin, Mosaicism, Child, Preschool, Female, Male, Proto-Oncogene Proteins c-akt, Phosphatidylinositol 3-Kinases, Class I Phosphatidylinositol 3-Kinases, Megalencephaly
Sponsorship
Wellcome Trust (095515/Z/11/Z)
MRC (MC_UU_12015/1)
MRC (MC_UU_12015/5)
MRC (MC_UU_12012/5)
Wellcome Trust (098498/Z/12/Z)
Identifiers
External DOI: https://doi.org/10.1530/eje-17-0132
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266663
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International