A Family with Severe Insulin Resistance and Diabetes Due to a Mutation in AKT2

• Published in: Science (American Association for the Advancement of Science) 2004-05, Vol.304 (5675), p.1325-1328
• Main Authors: George, Stella, Rochford, Justin J., Wolfrum, Christian, Gray, Sarah L., Schinner, Sven, Wilson, Jenny C., Soos, Maria A., Murgatroyd, Peter R., Williams, Rachel M., Acerini, Carlo L., Dunger, David B., Barford, David, Umpleby, A. Margot, Wareham, Nicholas J., Davies, Huw Alban, Schafer, Alan J., Stoffel, Markus, O'Rahilly, Stephen, Barroso, Inês
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adult; Aged; Amino Acid Motifs; Amino Acid Sequence; Amino Acid Substitution; Biological and medical sciences; Body Composition; Catalytic Domain; Cell Differentiation; Cell Line; Cell Nucleus - metabolism; Cytosol - metabolism; Deoxyribonucleic acid; Diabetes; Diabetes mellitus; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Diabetes. Impaired glucose tolerance; DNA; DNA-Binding Proteins - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Families & family life; Family (Sociological Unit); Female; Genes, Dominant; Genetic inheritance; Genetic mutation; Hep G2 cells; Hepatocyte Nuclear Factor 3-beta; Humans; Hyperinsulinism - genetics; Hyperinsulinism - metabolism; Individualized Instruction; Insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - genetics; Lipid Metabolism; Literary Devices; Liver; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Mutation; Mutation, Missense; Nuclear Proteins - metabolism; Pedigree; Phosphorylation; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Signal Transduction; Transcription Factors; Type 2 diabetes mellitus
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1096706

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/PKBβ 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.