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.
Highlights
Context: The activating p.Glu17Lys mutation in AKT2, a kinase mediating many of insulin’s metabolic actions, causes hypoinsulinemic hypoglycemia and left-sided hemihypertrophy
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
Physiological study of two affected probands At the age of 17 years old, two male patients [designated patient 1 (P1) and patient 2 (P2)] whose early clinical courses were previously described [2] were reassessed. Both participants and their families remained very anxious about hypoglycemia; the severity of this had lessened since early life
Summary
In vivo studies Body composition was assessed using Lunar Prodigy dualenergy X-ray absorptiometry (GE Lunar). Hepatic triglyceride was assessed using proton magnetic resonance spectroscopy on a Siemens 3T Verio scanner using methods previously described [9] and quantified as the ratio of methylene to combined methylene and water signals corrected for spin-spin relaxation. Adipose distribution was determined by magnetic resonance imaging using T1-weighted turbo spin echo, water-suppressed, transaxial images, generated by a Siemens 3T Verio scanner and pseudocolored for visualization using MATLAB software (The MathWorks, Inc., Natick, MA). The fractional de novo synthetic rate of fatty acids was determined by assessing the incorporation of deuterium into plasma triglyceride after the administration of deuterium-labeled water. A reference range was determined from nine healthy volunteers [9, 10]
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