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PMID: 15166380 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A family with severe insulin resistance and diabetes due to a mutation in AKT2.

Science (New York, N.Y.) ·Vol. 304 ·No. 5675 ·2004-05-28 ·Pages 1325-8

George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, O'Rahilly S, Barroso I

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.

MeSH Terms
Active Transport, Cell Nucleus Adipocytes/cytology,metabolism Adult Aged Amino Acid Motifs Amino Acid Sequence Amino Acid Substitution Catalytic Domain Cell Differentiation Cell Line Cell Nucleus/metabolism Cytosol/metabolism DNA-Binding Proteins/metabolism Diabetes Mellitus/genetics,metabolism Female Genes, Dominant Hepatocyte Nuclear Factor 3-beta Humans Hyperinsulinism/genetics,metabolism Insulin/metabolism Insulin Resistance/genetics Lipid Metabolism Male Middle Aged Molecular Sequence Data Mutation, Missense Nuclear Proteins/metabolism Pedigree Phosphorylation Protein Serine-Threonine Kinases/chemistry,genetics,metabolism Proto-Oncogene Proteins/chemistry,genetics,metabolism Proto-Oncogene Proteins c-akt Signal Transduction Transcription Factors
Chemicals
DNA-Binding Proteins FOXA2 protein, human Insulin Nuclear Proteins Proto-Oncogene Proteins Transcription Factors Hepatocyte Nuclear Factor 3-beta AKT1 protein, human AKT2 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
George Stella
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
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
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1096706
Published
2004-05-28
Pages
1325-8
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC2258004
Subset
IM
Grants
Wellcome Trust · 078986 · United Kingdom
Databases
GENBANK
M77198
External Links
PubMed source DOI: 10.1126/science.1096706 PMC Full Text View journal details
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