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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Adipocytes / cytology
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Adipocytes / metabolism
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Adult
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Aged
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Amino Acid Motifs
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Amino Acid Sequence
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Amino Acid Substitution
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Catalytic Domain
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Cell Differentiation
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Cell Line
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Cell Nucleus / metabolism
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Cytosol / metabolism
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DNA-Binding Proteins / metabolism
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Diabetes Mellitus / genetics*
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Diabetes Mellitus / metabolism
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Female
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Genes, Dominant
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Hepatocyte Nuclear Factor 3-beta
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Humans
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Hyperinsulinism / genetics
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Hyperinsulinism / metabolism
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Insulin / metabolism
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Insulin Resistance / genetics*
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Lipid Metabolism
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Male
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Middle Aged
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Molecular Sequence Data
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Mutation, Missense*
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Nuclear Proteins / metabolism
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Pedigree
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Phosphorylation
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction
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Transcription Factors*
Substances
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DNA-Binding Proteins
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FOXA2 protein, human
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Insulin
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Nuclear Proteins
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Proto-Oncogene Proteins
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Transcription Factors
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Hepatocyte Nuclear Factor 3-beta
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AKT1 protein, human
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AKT2 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt