A Low-Frequency InactivatingAKT2Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) inAKT2and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants inAKT2associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain ofAKT2.
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.
Alisa
A
Manning
Human Genetics Center, The University of Texas MD Anderson Cancer Center and The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX.|Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
Heather M
HM
Highland
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Jessica
J
Gasser
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.|Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
Xueling
X
Sim
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.|Department of Genetics, Harvard Medical School, Boston, MA.
Taru
T
Tukiainen
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|23andMe, Mountain View, CA.
Pierre
P
Fontanillas
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Niels
N
Grarup
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Manuel A
MA
Rivas
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Anubha
A
Mahajan
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Adam E
AE
Locke
School of Computer Science, McGill University, Montreal, Canada.|McGill University and Génome Québec Innovation Centre, Montreal, Canada.
Pablo
P
Cingolani
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Divisions of Endocrinology and Genetics and Genomics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA.|Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Tune H
TH
Pers
Department of Twin Research & Genetic Epidemiology, King's College London, London, U.K.|Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.|Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland.
Ana
A
Viñuela
Wellcome Trust Sanger Institute, Hinxton, U.K.|Norwegian Centre for Mental Disorders Research and KG Jebsen Center for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Andrew A
AA
Brown
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
Ying
Y
Wu
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Department of Molecular Biology, Massachusetts General Hospital, Boston, MA.
Jason
J
Flannick
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Christian
C
Fuchsberger
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL.|Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Eric R
ER
Gamazon
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Department of Pediatrics, University of California, San Diego, La Jolla, CA.
Kyle J
KJ
Gaulton
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL.
Hae Kyung
HK
Im
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Tanya M
TM
Teslovich
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Thomas W
TW
Blackwell
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jette
J
Bork-Jensen
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Noël P
NP
Burtt
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Yuhui
Y
Chen
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Todd
T
Green
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Christopher
C
Hartl
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Hyun Min
HM
Kang
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Chronic Disease Epidemiology Unit, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
Ashish
A
Kumar
Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden.
Claes
C
Ladenvall
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Clement
C
Ma
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Loukas
L
Moutsianas
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Richard D
RD
Pearson
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.|MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
John R B
JRB
Perry
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.|Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.
N William
NW
Rayner
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
Neil R
NR
Robertson
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Laura J
LJ
Scott
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
Martijn
M
van de Bunt
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.|Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.|Folkhälsan Research Center, Helsinki, Finland.|Vaasa Central Hospital, Vaasa, Finland.|Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Johan G
JG
Eriksson
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Antti
A
Jula
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Seppo
S
Koskinen
Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland.
Terho
T
Lehtimäki
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA.|Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Aarno
A
Palotie
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.|Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
Olli T
OT
Raitakari
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Suzanne B R
SBR
Jacobs
Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN.|Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
Jennifer
J
Wessel
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA.
Audrey Y
AY
Chu
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
Robert A
RA
Scott
Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
Mark O
MO
Goodarzi
High-Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Christine
C
Blancher
High-Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Gemma
G
Buck
High-Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
David
D
Buck
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Peter S
PS
Chines
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Stacey
S
Gabriel
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Anette P
AP
Gjesing
Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
Christopher J
CJ
Groves
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Mette
M
Hollensted
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Jeroen R
JR
Huyghe
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Anne U
AU
Jackson
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Goo
G
Jun
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Johanne Marie
JM
Justesen
Department of Twin Research & Genetic Epidemiology, King's College London, London, U.K.
Massimo
M
Mangino
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Jacquelyn
J
Murphy
Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
Matt
M
Neville
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Robert
R
Onofrio
Department of Twin Research & Genetic Epidemiology, King's College London, London, U.K.
Kerrin S
KS
Small
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Heather M
HM
Stringham
High-Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Joseph
J
Trakalo
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Eric
E
Banks
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Jason
J
Carey
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Mauricio O
MO
Carneiro
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Mark
M
DePristo
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Yossi
Y
Farjoun
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Timothy
T
Fennell
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.
Jacqueline I
JI
Goldstein
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
George
G
Grant
Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising, Germany.
Martin
M
Hrabé de Angelis
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Jared
J
Maguire
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.
Benjamin M
BM
Neale
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Ryan
R
Poplin
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA.|Department of Psychiatry, Icahn Institute for Genomics & Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
Shaun
S
Purcell
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Thomas
T
Schwarzmayr
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
Khalid
K
Shakir
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA.
Joshua D
JD
Smith
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Neuherberg, Germany.
Tim M
TM
Strom
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Thomas
T
Wieland
Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
Jaana
J
Lindstrom
Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.|Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark.
Ivan
I
Brandslund
Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.
Cramer
C
Christensen
Department of Twin Research & Genetic Epidemiology, King's College London, London, U.K.
Gabriela L
GL
Surdulescu
Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.|Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.|Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
Timo A
TA
Lakka
Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K.
Alex S F
ASF
Doney
Department of Clinical Sciences, Faculty of Medicine, Lund University, Malmö, Sweden.
Peter
P
Nilsson
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
Nicholas J
NJ
Wareham
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
Claudia
C
Langenberg
Department of Clinical Sciences, Lund University Diabetes Centre, and Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
Tibor V
TV
Varga
Department of Clinical Sciences, Lund University Diabetes Centre, and Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.|Department of Nutrition, Harvard School of Public Health, Boston, MA.|Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
Paul W
PW
Franks
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
Olov
O
Rolandsson
Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden.
Anders H
AH
Rosengren
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
Vidya S
VS
Farook
Department of Medicine, The University of Texas Health Science Center, San Antonio, TX.
Farook
F
Thameem
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
Sobha
S
Puppala
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
Satish
S
Kumar
Department of Medicine, The University of Texas Health Science Center, San Antonio, TX.
Donna M
DM
Lehman
Department of Medicine, The University of Texas Health Science Center, San Antonio, TX.|Research and Development Service, South Texas Veterans Health Care System, San Antonio, TX.
Christopher P
CP
Jenkinson
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
Joanne E
JE
Curran
Department of Pediatrics, The University of Texas Health Science Center, San Antonio, TX.
Daniel Esten
DE
Hale
Department of Medicine, The University of Texas Health Science Center, San Antonio, TX.
Sharon P
SP
Fowler
Department of Pediatrics, The University of Texas Health Science Center, San Antonio, TX.
Rector
R
Arya
Department of Medicine, The University of Texas Health Science Center, San Antonio, TX.
Ralph A
RA
DeFronzo
Department of Medicine, The University of Texas Health Science Center, San Antonio, TX.
Hanna E
HE
Abboud
Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Ann-Christine
AC
Syvänen
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC.
Pamela J
PJ
Hicks
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC.
Nicholette D
ND
Palmer
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC.
Maggie C Y
MCY
Ng
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC.
Donald W
DW
Bowden
Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
Barry I
BI
Freedman
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Department of Genetics, Harvard Medical School, Boston, MA.|Division of Endocrinology, Boston Children's Hospital, Boston, MA.|Estonian Genome Center, University of Tartu, Tartu, Estonia.
Tõnu
T
Esko
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Reedik
R
Mägi
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Lili
L
Milani
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Evelin
E
Mihailov
Estonian Genome Center, University of Tartu, Tartu, Estonia.
Andres
A
Metspalu
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Narisu
N
Narisu
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Leena
L
Kinnunen
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Lori L
LL
Bonnycastle
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Amy
A
Swift
Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
Dorota
D
Pasko
Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
Andrew R
AR
Wood
Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden.
João
J
Fadista
Program in Personalized and Genomic Medicine, Department of Medicine, University of Maryland, Baltimore, MD.
Toni I
TI
Pollin
Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY.
Nir
N
Barzilai
Departments of Medicine and Genetics, Albert Einstein College of Medicine, New York, NY.|Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
Gil
G
Atzmon
Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Benjamin
B
Glaser
German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Barbara
B
Thorand
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
Konstantin
K
Strauch
German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
Annette
A
Peters
Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.|German Center for Diabetes Research, Partner Düsseldorf, Germany.
Michael
M
Roden
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.|Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.|Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
Martina
M
Müller-Nurasyid
Department of Epidemiology, Harvard School of Public Health, Boston, MA.|Department of Biostatistics, Harvard School of Public Health, Boston, MA.
Liming
L
Liang
German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Jennifer
J
Kriebel
Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.|Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
Thomas
T
Illig
German Center for Diabetes Research (DZD), Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Harald
H
Grallert
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Christian
C
Gieger
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Christa
C
Meisinger
Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
Lars
L
Lannfelt
Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS.
Solomon K
SK
Musani
Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS.
Michael
M
Griswold
Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
Herman A
HA
Taylor
College of Public Services, Jackson State University, Jackson, MS.
Gregory
G
Wilson
Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
Adolfo
A
Correa
Pirkanmaa Hospital District, Tampere, Finland.
Heikki
H
Oksa
Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.
William R
WR
Scott
Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.
Uzma
U
Afzal
Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, U.K.|Department of Cardiology, Ealing Hospital NHS Trust, Southall, U.K.
Sian-Tsung
ST
Tan
Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.|Institute of Health Sciences, University of Oulu, Oulu, Finland.|Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR), Singapore.
Marie
M
Loh
Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.|Department of Cardiology, Ealing Hospital NHS Trust, Southall, U.K.|Imperial College Healthcare NHS Trust, Imperial College London, London, U.K.
John C
JC
Chambers
Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, U.K.|Department of Cardiology, Ealing Hospital NHS Trust, Southall, U.K.
Jobanpreet
J
Sehmi
Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, U.K.
Jaspal Singh
JS
Kooner
Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.
Benjamin
B
Lehne
Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea.
Yoon Shin
YS
Cho
Ministry of Health and Welfare, Seoul, Republic of Korea.
Jong-Young
JY
Lee
Center for Genome Science, Korea National Research Institute of Health, Chungcheongbuk-do, Republic of Korea.
Bok-Ghee
BG
Han
Vaasa Health Care Center, Vaasa, Finland.|Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland.
Annemari
A
Käräjämäki
Department of Nutrition, Harvard School of Public Health, Boston, MA.|Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY.
Qibin
Q
Qi
Department of Nutrition, Harvard School of Public Health, Boston, MA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Lu
L
Qi
Department of Epidemiology, Harvard School of Public Health, Boston, MA.
Jinyan
J
Huang
Department of Nutrition, Harvard School of Public Health, Boston, MA.|Department of Epidemiology, Harvard School of Public Health, Boston, MA.
Frank B
FB
Hu
Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Olle
O
Melander
Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Marju
M
Orho-Melander
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Jennifer E
JE
Below
Cardiovascular Division, Baylor College of Medicine, Houston, TX.
David
D
Aguilar
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Tien Yin
TY
Wong
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.|Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore.
Jianjun
J
Liu
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.|Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore.|Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Chiea-Chuen
CC
Khor
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
Kee Seng
KS
Chia
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
Wei Yen
WY
Lim
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.|Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Office of Clinical Sciences, Centre for Quantitative Medicine, Duke-NUS Graduate Medical School Singapore, Singapore.
Ching-Yu
CY
Cheng
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Edmund
E
Chan
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore.
E Shyong
ES
Tai
Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Tin
T
Aung
Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.|Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Allan
A
Linneberg
Folkhälsan Research Center, Helsinki, Finland.|Department of Social Services and Health Care, Jakobstad, Finland.
Bo
B
Isomaa
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, Neuherberg, Germany.|Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
Thomas
T
Meitinger
Folkhälsan Research Center, Helsinki, Finland.|Department of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland.
Tiinamaija
T
Tuomi
Folkhälsan Research Center, Helsinki, Finland.
Liisa
L
Hakaste
Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden.
Jasmina
J
Kravic
Steno Diabetes Center, Gentofte, Denmark.
Marit E
ME
Jørgensen
Section of General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark.
Torsten
T
Lauritzen
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.
Panos
P
Deloukas
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.|Department of Haematology, University of Cambridge, Cambridge, U.K.
Kathleen E
KE
Stirrups
Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.|Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
Katharine R
KR
Owen
Department of Primary Care Health Sciences, University of Oxford, Oxford, U.K.
Andrew J
AJ
Farmer
Genetics of Complex Traits, University of Exeter Medical School, Exeter, U.K.
Timothy M
TM
Frayling
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
Stephen P
SP
O'Rahilly
Institute of Cellular Medicine, University of Newcastle, Newcastle, U.K.
Mark
M
Walker
Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
Jonathan C
JC
Levy
Department of Twin Research & Genetic Epidemiology, King's College London, London, U.K.
Dylan
D
Hodgkiss
University of Exeter Medical School, Exeter, U.K.
Andrew T
AT
Hattersley
Internal Medicine, Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Teemu
T
Kuulasmaa
Internal Medicine, Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Alena
A
Stančáková
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.|Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
Inês
I
Barroso
Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology, New Delhi, India.
Dwaipayan
D
Bharadwaj
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.|Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China.
Juliana
J
Chan
CSIR-Centre for Cellular & Molecular Biology, Hyderabad, India.
Giriraj R
GR
Chandak
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.
Mark J
MJ
Daly
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Department of Statistics, University of Oxford, Oxford, U.K.
Peter J
PJ
Donnelly
Centre for Chronic Disease Control, New Delhi, India.
Shah B
SB
Ebrahim
Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.|MRC-PHE Centre for Environment & Health, Imperial College London, London, U.K.
Paul
P
Elliott
Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO.
Tasha
T
Fingerlin
Genomics and Molecular Physiology, CNRS Institut de Biologie de Lille, Lille, France.
Philippe
P
Froguel
Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Cheng
C
Hu
Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Weiping
W
Jia
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.|Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.|Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China.
Ronald C W
RCW
Ma
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
Gilean
G
McVean
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea.|Department of Statistics, Seoul National University, Seoul, Republic of Korea.
Taesung
T
Park
Centre for Chronic Disease Control, New Delhi, India.
Dorairaj
D
Prabhakaran
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.|Institute of Public Health, Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.
Manjinder
M
Sandhu
Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, London, U.K.
James
J
Scott
McGill University and Génome Québec Innovation Centre, Montreal, Canada.|Department of Human Genetics, McGill University, Montreal, Canada.|Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, Canada.
Rob
R
Sladek
Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.
Nikhil
N
Tandon
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.|Life Sciences Institute, National University of Singapore, Singapore.|Department of Statistics and Applied Probability, National University of Singapore, Singapore.
Yik Ying
YY
Teo
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.
Eleftheria
E
Zeggini
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA.|Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.|Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Richard M
RM
Watanabe
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.|Department of Medicine and Abdominal Center, Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Heikki A
HA
Koistinen
Institute of Clinical Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
Y Antero
YA
Kesaniemi
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
Matti
M
Uusitupa
Department of Twin Research & Genetic Epidemiology, King's College London, London, U.K.
Timothy D
TD
Spector
Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Veikko
V
Salomaa
Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
Rainer
R
Rauramaa
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, U.K.
Colin N A
CNA
Palmer
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.|Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, U.K.
Inga
I
Prokopenko
Division for Molecular Medicine, Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, U.K.
Andrew D
AD
Morris
Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Richard N
RN
Bergman
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
Francis S
FS
Collins
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Lars
L
Lind
Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.|Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
Erik
E
Ingelsson
Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.|Center for Vascular Prevention, Danube University Krems, Krems, Austria.|Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.|Dasman Diabetes Institute, Dasman, Kuwait.
Jaakko
J
Tuomilehto
Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.|Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
Fredrik
F
Karpe
Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Malmö, Sweden.
Leif
L
Groop
Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.|Faculty of Medicine, University of Aalborg, Aalborg, Denmark.
Torben
T
Jørgensen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.|Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
Torben
T
Hansen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Oluf
O
Pedersen
Internal Medicine, Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.|Kuopio University Hospital, Kuopio, Finland.
Johanna
J
Kuusisto
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Gonçalo
G
Abecasis
Departments of Medicine and Human Genetics, The University of Chicago, Chicago, IL.
Graeme I
GI
Bell
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
John
J
Blangero
Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL.
Nancy J
NJ
Cox
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
Ravindranath
R
Duggirala
Department of Laboratory Medicine, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA.|Blood Systems Research Institute, San Francisco, CA.
Mark
M
Seielstad
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS.
James G
JG
Wilson
Department of Biostatistics, Boston University School of Public Health, Boston, MA.|Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.
Josee
J
Dupuis
Wellcome Trust Sanger Institute, Hinxton, U.K.|Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.|Hjelt Institute, University of Helsinki, Helsinki, Finland.
Samuli
S
Ripatti
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Craig L
CL
Hanis
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.|Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA.
Jose C
JC
Florez
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
Karen L
KL
Mohlke
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Department of Medicine, Harvard Medical School, Boston, MA.|Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
James B
JB
Meigs
Internal Medicine, Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.|Kuopio University Hospital, Kuopio, Finland.
Markku
M
Laakso
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Estonian Genome Center, University of Tartu, Tartu, Estonia.|Department of Biostatistics, University of Liverpool, Liverpool, U.K.
Andrew P
AP
Morris
Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI.
Michael
M
Boehnke
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Department of Medicine, Harvard Medical School, Boston, MA.|Department of Genetics, Harvard Medical School, Boston, MA.|Department of Molecular Biology, Massachusetts General Hospital, Boston, MA.|Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA.
David
D
Altshuler
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.|Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
Mark I
MI
McCarthy
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.|Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.
Anna L
AL
Gloyn
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.|Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.|Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, U.K.
Cecilia M
CM
Lindgren
D001741:Black or African American / Q000235:genetics; D000483:Alleles; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005215:Fasting / Q000378:metabolism*; D005387:Finland; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D016017:Odds Ratio; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D044465:White People / Q000235:genetics*
D007328:Insulin; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt