Hypoglycemia is normally caused by increased insulin secretion, increased activation of insulin receptors or congenital underproduction of glucose. The effects of insulin are mediated by a signaling pathway involving AKT2 activation. Hussein and colleagues identified a mutation in the AKT2 gene in three individuals with unexplained hypoglycemia whose parents do not carry the mutation. This mutation leads to transmembrane localization and constitutive activation of AKT2 and, as a result, to hypoglycemia that is independent of insulin.