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

Stella George; Justin J Rochford; Christian Wolfrum; Sarah L Gray; Sven Schinner; Jenny C Wilson; Maria A Soos; Peter R Murgatroyd; Rachel M Williams; Carlo L Acerini; David B Dunger; David Barford; A Margot Umpleby; Nicholas J Wareham; Huw Alban Davies; Alan J Schafer; Markus Stoffel; Stephen O'Rahilly; Inês Barroso

doi:10.1126/science.1096706

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

Stella George, Justin J Rochford, Christian Wolfrum, Sarah L Gray, Sven Schinner, Jenny C Wilson, Maria A Soos, Peter R Murgatroyd, Rachel M Williams, Carlo L Acerini, David B Dunger, David Barford, A Margot Umpleby, Nicholas J Wareham, Huw Alban Davies, Alan J Schafer, Markus Stoffel, Stephen O'Rahilly, Inês Barroso

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

458 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1325-1328
Number of pages	4
Journal	Science
Volume	304
Issue number	5675
DOIs	https://doi.org/10.1126/science.1096706
Publication status	Published - 28 May 2004

Keywords

Active Transport, Cell Nucleus
Adipocytes
Adult
Aged
Amino Acid Motifs
Amino Acid Sequence
Amino Acid Substitution
Catalytic Domain
Cell Differentiation
Cell Line
Cell Nucleus
Cytosol
DNA-Binding Proteins
Diabetes Mellitus
Female
Genes, Dominant
Hepatocyte Nuclear Factor 3-beta
Humans
Hyperinsulinism
Insulin
Insulin Resistance
Lipid Metabolism
Male
Middle Aged
Molecular Sequence Data
Mutation, Missense
Nuclear Proteins
Pedigree
Phosphorylation
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
Signal Transduction
Transcription Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/science.1096706

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George, S., Rochford, J. J., Wolfrum, C., Gray, S. L., Schinner, S., Wilson, J. C., Soos, M. A., Murgatroyd, P. R., Williams, R. M., Acerini, C. L., Dunger, D. B., Barford, D., Umpleby, A. M., Wareham, N. J., Davies, H. A., Schafer, A. J., Stoffel, M., O'Rahilly, S., & Barroso, I. (2004). A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science, 304(5675), 1325-1328. https://doi.org/10.1126/science.1096706

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 2004, 'A family with severe insulin resistance and diabetes due to a mutation in AKT2', Science, vol. 304, no. 5675, pp. 1325-1328. https://doi.org/10.1126/science.1096706

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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.",

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author = "Stella George and Rochford, {Justin J} and Christian Wolfrum and Gray, {Sarah L} and Sven Schinner and Wilson, {Jenny C} and Soos, {Maria A} and Murgatroyd, {Peter R} and Williams, {Rachel M} and Acerini, {Carlo L} and Dunger, {David B} and David Barford and Umpleby, {A Margot} and Wareham, {Nicholas J} and Davies, {Huw Alban} and Schafer, {Alan J} and Markus Stoffel and Stephen O'Rahilly and In{\^e}s Barroso",

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AU - George, Stella

AU - Rochford, Justin J

AU - Wolfrum, Christian

AU - Gray, Sarah L

AU - Schinner, Sven

AU - Wilson, Jenny C

AU - Soos, Maria A

AU - Murgatroyd, Peter R

AU - Williams, Rachel M

AU - Acerini, Carlo L

AU - Dunger, David B

AU - Barford, David

AU - Umpleby, A Margot

AU - Wareham, Nicholas J

AU - Davies, Huw Alban

AU - Schafer, Alan J

AU - Stoffel, Markus

AU - O'Rahilly, Stephen

AU - Barroso, Inês

PY - 2004/5/28

Y1 - 2004/5/28

N2 - 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.

AB - 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.

KW - Active Transport, Cell Nucleus

KW - Adipocytes

KW - Adult

KW - Aged

KW - Amino Acid Motifs

KW - Amino Acid Sequence

KW - Amino Acid Substitution

KW - Catalytic Domain

KW - Cell Differentiation

KW - Cell Line

KW - Cell Nucleus

KW - Cytosol

KW - DNA-Binding Proteins

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KW - Female

KW - Genes, Dominant

KW - Hepatocyte Nuclear Factor 3-beta

KW - Humans

KW - Hyperinsulinism

KW - Insulin

KW - Insulin Resistance

KW - Lipid Metabolism

KW - Male

KW - Middle Aged

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Nuclear Proteins

KW - Pedigree

KW - Phosphorylation

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins

KW - Proto-Oncogene Proteins c-akt

KW - Signal Transduction

KW - Transcription Factors

U2 - 10.1126/science.1096706

DO - 10.1126/science.1096706

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VL - 304

SP - 1325

EP - 1328

JO - Science

JF - Science

IS - 5675

ER -

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

Abstract

Keywords

UN SDGs

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