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A Family with Severe Insulin Resistance and Diabetes Due to a Mutation in AKT2
Stella George,1*Justin J. Rochford,1*Christian Wolfrum,3Sarah L. Gray,1Sven Schinner,1Jenny C. Wilson,1Maria A. Soos,1Peter R. Murgatroyd,1Rachel M. Williams,2Carlo L. Acerini,2David B. Dunger,2David Barford,4A. Margot Umpleby,5Nicholas J. Wareham,6Huw Alban Davies,7Alan J. Schafer,8Markus Stoffel,3Stephen O'Rahilly,1Inês Barroso8,9
Inherited defects in signaling pathways downstream of the insulinreceptor have long been suggested to contribute to human type2 diabetes mellitus. Here we describe a mutation in the geneencoding the protein kinase AKT2/PKBß in a familythat shows autosomal dominant inheritance of severe insulinresistance and diabetes mellitus. Expression of the mutant kinasein cultured cells disrupted insulin signaling to metabolic endpoints and inhibited the function of coexpressed, wild-typeAKT. These findings demonstrate the central importance of AKTsignaling to insulin sensitivity in humans.
1 Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. 2 Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. 3 Laboratory of Metabolic Diseases, Rockefeller University, New York, NY 10021, USA. 4 Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK. 5 Department of Diabetes, Endocrinology and Internal Medicine, Guy's, King's and St. Thomas' School of Medicine, London, UK. 6 Medical Research Council Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK. 7 Darent Valley Hospital, Darenth Wood Road, Dartford, Kent DA2 8DA, UK. 8 Incyte, 3160 Porter Drive, Palo Alto, CA 94304, USA. 9 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: sorahill{at}hgmp.mrc.ac.uk
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To whom correspondence should be addressed. E-mail: 
