A family with severe insulin resistance and diabetes due to a mutation in AKT2.
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.
George
Stella
S
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
Rochford
Justin J
JJ
Wolfrum
Christian
C
Gray
Sarah L
SL
Schinner
Sven
S
Wilson
Jenny C
JC
Soos
Maria A
MA
Murgatroyd
Peter R
PR
Williams
Rachel M
RM
Acerini
Carlo L
CL
Dunger
David B
DB
Barford
David
D
Umpleby
A Margot
AM
Wareham
Nicholas J
NJ
Davies
Huw Alban
HA
Schafer
Alan J
AJ
Stoffel
Markus
M
O'Rahilly
Stephen
S
Barroso
Inês
I
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
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