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An Activating Mutation of AKT2 and Human Hypoglycemia

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Science  06 Oct 2011:
1210878
DOI: 10.1126/science.1210878

Abstract

Pathological fasting hypoglycemia in humans is usually explained by excessive circulating insulin or insulin-like molecules, or by inborn errors of metabolism impairing liver glucose production. We studied three unrelated children with unexplained, recurrent, and severe fasting hypoglycemia and asymmetrical growth. All were found to carry the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2, in two cases as heterozygotes and, in one case, in mosaic form. In heterologous cells, the mutant AKT2 was constitutively recruited to the plasma membrane, leading to insulin-independent activation of downstream signaling. Thus, systemic metabolic disease can result from constitutive, cell-autonomous activation of signaling pathways normally controlled by insulin.