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Science 28 May 2004:
Vol. 304. no. 5675, pp. 1325 - 1328
DOI: 10.1126/science.1096706
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Reports

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

Stella George,1* Justin J. Rochford,1* Christian Wolfrum,3 Sarah L. Gray,1 Sven Schinner,1 Jenny C. Wilson,1 Maria A. Soos,1 Peter R. Murgatroyd,1 Rachel M. Williams,2 Carlo L. Acerini,2 David B. Dunger,2 David Barford,4 A. Margot Umpleby,5 Nicholas J. Wareham,6 Huw Alban Davies,7 Alan J. Schafer,8 Markus Stoffel,3 Stephen O'Rahilly,1{dagger} Inês Barroso8,9

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/PKBß 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.

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.

{dagger} To whom correspondence should be addressed. E-mail: sorahill{at}hgmp.mrc.ac.uk

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