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

Abstract

$\textbf{Context:}$ 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. $\textbf{Objective:}$ To characterize the metabolic and cellular consequences of the AKT2 p.Glu17Lys mutation in two previously reported males at the age of 17 years. $\textbf{Design and Intervention:}$ 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 $\textit{de novo}$ lipogenesis was quantified using deuterium incorporationinto palmitate. Signalingin dermal fibroblasts was studied $\textit{ex vivo}$. $\textbf{Results:}$ 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 $\textit{de novo}$ 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. $\textbf{Conclusions:}$ 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 $\textit{de novo}$ lipogenesis. Hypoglycemia may spontaneously remit.This work was supported by Wellcome Trust Grant WT098498, the Medical Research Council (MRC_MC_UU_12012/5), the United Kingdom National Institute for Health Research Cambridge Biomedical Research Centre, the European Union/ European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative Joint Undertaking (European Medical Information Framework Grant 115372), and the Cambridge Gates Foundation