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

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    362 Citations (Scopus)

    Abstract

    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
    JournalScience
    Volume304
    Issue number5675
    DOIs
    Publication statusPublished - 28 May 2004

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    Keywords

    • 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

    Cite this

    George, S., Rochford, J. J., Wolfrum, C., Gray, S. L., Schinner, S., Wilson, J. C., Soos, M. A., Murgatroyd, P. R., Williams, R. M., Acerini, C. L., Dunger, D. B., Barford, D., Umpleby, A. M., Wareham, N. J., Davies, H. A., Schafer, A. J., Stoffel, M., O'Rahilly, S., & Barroso, I. (2004). A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science, 304(5675), 1325-1328. https://doi.org/10.1126/science.1096706