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J Clin Endocrinol Metab. 2017 Aug 1;102(8):2914-2921. doi: 10.1210/jc.2017-00768.

Constitutive Activation of AKT2 in Humans Leads to Hypoglycemia Without Fatty Liver or Metabolic Dyslipidemia.

Author information

1
The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council (MRC) Institute of Metabolic Science, Cambridge CB2 0QQ, United Kingdom.
2
The National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, United Kingdom.
3
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom.
4
Wolfson Brain Imaging Centre, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
5
National Institute for Health Research/Wellcome Trust Clinical Research Facility, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, United Kingdom.
6
Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, 75270 Paris Cedex 06, France.
7
Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
8
Institut Imagine, Institut National de la Sante et de la Recherche Médicale, Unité 1163, 75015 Paris, France.
9
Department of Pediatric Medicine, Sidra Medical and Research Center, PO Box 26999, Doha, Qatar.

Abstract

Context:

The activating p.Glu17Lys mutation in AKT2, a kinase mediating many of insulin's metabolic actions, causes hypoinsulinemic hypoglycemia and left-sided hemihypertrophy. The wider metabolic profile and longer-term natural history of the condition has not yet been reported.

Objective:

To characterize the metabolic and cellular consequences of the AKT2 p.Glu17Lys mutation in two previously reported males at the age of 17 years.

Design and Intervention:

Body composition analysis using dual-energy X-ray absorptiometry, overnight profiling of plasma glucose, insulin, and fatty acids, oral glucose tolerance testing, and magnetic resonance spectroscopy to determine hepatic triglyceride content was undertaken. Hepatic de novo lipogenesis was quantified using deuterium incorporation into palmitate. Signaling in dermal fibroblasts was studied ex vivo.

Results:

Both patients had 37% adiposity. One developed hypoglycemia after 2 hours of overnight fasting with concomitant suppression of plasma fatty acids and ketones, whereas the other maintained euglycemia with an increase in free fatty acids. Blood glucose excursions after oral glucose were normal in both patients, albeit with low plasma insulin concentrations. In both patients, plasma triglyceride concentration, hepatic triglyceride content, and fasting hepatic de novo lipogenesis were normal. Dermal fibroblasts of one proband showed low-level constitutive phosphorylation of AKT and some downstream substrates, but no increased cell proliferation rate.

Conclusions:

The p.Glu17Lys mutation of AKT2 confers low-level constitutive activity upon the kinase and produces hypoglycemia with suppressed fatty acid release from adipose tissue, but not fatty liver, hypertriglyceridemia, or elevated hepatic de novo lipogenesis. Hypoglycemia may spontaneously remit.

PMID:
28541532
PMCID:
PMC5546860
DOI:
10.1210/jc.2017-00768
[Indexed for MEDLINE]
Free PMC Article

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