A family with severe insulin resistance and diabetes due to a mutation in AKT2

Stella George, Justin J Rochford, Christian Wolfrum, Sarah L Gray, Sven Schinner, Jenny C Wilson, Maria A Soos, Peter R Murgatroyd, Rachel M Williams, Carlo L Acerini, David B Dunger, David Barford, A Margot Umpleby, Nicholas J Wareham, Huw Alban Davies, Alan J Schafer, Markus Stoffel, Stephen O'Rahilly, Inês Barroso

Research output: Contribution to journalArticlepeer-review

458 Citations (Scopus)


Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.
Original languageEnglish
Pages (from-to)1325-1328
Number of pages4
Issue number5675
Publication statusPublished - 28 May 2004


  • Active Transport, Cell Nucleus
  • Adipocytes
  • Adult
  • Aged
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Catalytic Domain
  • Cell Differentiation
  • Cell Line
  • Cell Nucleus
  • Cytosol
  • DNA-Binding Proteins
  • Diabetes Mellitus
  • Female
  • Genes, Dominant
  • Hepatocyte Nuclear Factor 3-beta
  • Humans
  • Hyperinsulinism
  • Insulin
  • Insulin Resistance
  • Lipid Metabolism
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation, Missense
  • Nuclear Proteins
  • Pedigree
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Transcription Factors


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