title: A family with severe insulin resistance and diabetes due to a mutation in AKT2.
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.
authors.affiliation: Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Stella
authors.initials: S
authors.lastname: George
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Rochford
authors.forename: Christian
authors.initials: C
authors.lastname: Wolfrum
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gray
authors.forename: Sven
authors.initials: S
authors.lastname: Schinner
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Wilson
authors.forename: Maria A
authors.initials: MA
authors.lastname: Soos
authors.forename: Peter R
authors.initials: PR
authors.lastname: Murgatroyd
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Williams
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Acerini
authors.forename: David B
authors.initials: DB
authors.lastname: Dunger
authors.forename: David
authors.initials: D
authors.lastname: Barford
authors.forename: A Margot
authors.initials: AM
authors.lastname: Umpleby
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Huw Alban
authors.initials: HA
authors.lastname: Davies
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Schafer
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
mesh_terms: D021581:Active Transport, Cell Nucleus; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000328:Adult; D000368:Aged; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020134:Catalytic Domain; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000378:metabolism; D010375:Pedigree; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; D007328:Insulin; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt