Loss of AKT2 function in humans causes severe insulin resistance. A new study by Robert Semple and colleagues (Science 334, 474, 2011) now shows that gain-of-function AKT2 mutations result in severe hypoglycemia, weight gain and gross asymmetric overgrowth. The authors performed exome sequencing on a single individual with these phenotypic features and identified a heterozygous missense mutation in AKT2 that was absent from the unaffected parents. They then sequenced two additional unrelated individuals with the same constellation of features and found the identical AKT2 mutation in both individuals, of whom one was heterozygous for the mutation and one showed evidence of somatic mosaicism. In both instances, the mutation was absent from the unaffected parents. The mutation, which leads to a glutamate-to-lysine substitution at position 17 in the pleckstrin homology domain of AKT2, results in constitutive plasma membrane localization and activated signaling. Notably, somatic mosaicism for the AKT1 variant encoding an identical p.Glu17Lys substitution was recently shown to underlie the characteristic skin and skeletal overgrowth in Proteus syndrome (N. Engl. J. Med. 365, 611–619, 2011), highlighting the overlapping but distinct consequences of deregulated AKT1 and AKT2 signaling.