Journal
DIABETES
Volume 66, Issue 7, Pages 2019-2032Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db16-1329
Keywords
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Categories
Funding
- Academy of Finland [102318, 129293, 128315, 129330, 131593, 139635, 121584, 126925, 124282, 129378, 258753, 123885, 124243]
- Action on Hearing Loss [G51]
- Jalmari and Rauha Ahokas Foundation
- American Diabetes Association [7-12-MN-02]
- Archimedes Foundation [3.2.1001.11-0033]
- Atlantic Canada Opportunities Agency
- Augustinus Foundation
- Becket Foundation
- Alfred Benzon Foundation
- Biomedical Research Council
- British Heart Foundation [SP/04/002]
- Canada Foundation for Innovation
- City of Kuopio
- Social Insurance Institution of Finland [4/26/2010]
- Commission of the European Communities
- Directorate C-Public Health [2004310]
- Copenhagen County
- Danish Centre for Evaluation and Health Technology Assessment
- Danish Council for Independent Research
- Danish Heart Foundation [07-10-R61-A1754-B838-22392F]
- Danish Medical Research Council
- Danish Pharmaceutical Association (Dansk Apotekerforening)
- Development Fund of the University of Tartu [SP1GVARENG]
- Emil Aaltonen Foundation
- Estonian Research Council [IUT20-60]
- European Research Council
- European Commission [HEALTH-F2-2007-201681, HEALTH-F4-2007-201413, LSHM-CT-2004-005272, PIEF-GA-2012329156, 633589, 654248, 676550]
- European Commission FP6 (EXGENESIS)
- European Commission FP7 [279143, FP7/2007-2013, 259749, 278913]
- European Research Council Advanced Research Grant
- Finland's Slot Machine Association
- Finnish Cultural Foundation
- Finnish Diabetes Association
- Finnish Diabetes Research Foundation
- Finnish Foundation for Cardiovascular Research
- Finnish Foundation for Diabetes Research
- Finnish Heart Association
- Finnish Medical Society
- Finnish National Public Health Institute
- Finska Lakaresallskapet
- Folkhalsan Research Foundation
- Foundation for Life and Health in Finland
- German Center for Diabetes Research (DZD)
- German Federal Ministry of Education and Research
- State of Bavaria
- German Research Center for Environmental Health
- Guy's and St Thomas' NHS Foundation Trust
- health care center in Vaasa
- health care center in Narpes
- health care center in Korsholm
- Health Insurance Foundation (Helsefonden) [2012B233]
- Helmholtz Zentrum Munchen - German Research Center for Environmental Health
- Helsinki University Central Hospital Research Foundation
- hospital districts of Pirkanmaa
- Southern Ostrobothnia
- Northern Ostrobothnia
- Central Finland
- Northern Savonia
- Ib Henriksen Foundation
- Juho Vainio Foundation
- Korea Centers for Disease Control and Prevention [4845-301, 4851-302, 4851-307, KBP-2013-11, KBP-2014-68]
- Korea National Research Institute of Health [2012-N73002-00]
- Kuopio University Hospital
- Li Ka Shing Foundation
- Liv och Halsa
- Ludwig-Maximilians-Universitat as part of LMUinnovativ
- Lundbeck Foundation
- Medical Research Council [G0601261, G0900747-91070, G0601966, G0700931]
- Ministry of Education and Culture of Finland [627]
- Ministry of Social Affairs and Health in Finland
- MRC-PHE Centre for Environment and Health
- Munich Center of Health Sciences
- municipal health care center and hospital in Jakobstad
- Narpes Health Care Foundation
- National Institute for Health Research [RP-PG-0407-10371]
- National Cancer Institute/SAIC-Frederick, Inc. [10XS170, 10XS171, X10S172]
- National Cancer Institute [K12 CA1391602]
- National Heart, Lung, and Blood Institute [R01 HL102830, T32 HL007055]
- National Human Genome Research Institute [Z01 HG000024]
- National Institute on Aging [PO1 AG027734, R01 AG046949, 1R01 AG042188, P30 AG038072]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK066358, U01 DK062370, P30 DK020595, R01 DK073541, R01 DK078616, R01 DK098032, U01 DK085501, U01 DK085524, U01 DK085545, U01 DK085584, K24 DK080140, RC2 DK088389, U01 DK085526, DK072193]
- National Institute on Drug Abuse [R01 DA006227, R01 DA033684]
- National Institute of General Medical Sciences [T32 GM007753]
- National Institutes of Health [HHSN 268201300046C, HHSN 268201300047C, HHSN 268201300048C, HHSN 268201300049C, HHSN 268201300050C, HHSN 268201000029C, HHSN 261200800001E]
- National Institutes of Health Office of the Director [R01 MH101820, R01 MH090937, R01 MH090941, R01 MH101814, R01 MH090951, R01 MH101825, R01 MH090936, R01 MH101819, R01 MH090948, R01 MH101782, R01 MH101810, R01 MH101822]
- National Institute of Mental Health [R01 MH107666, N01 MH000028]
- Singapore National Medical Research Council
- National Research Foundation of Korea [NRF-2012R1A2A1A03006155]
- Nordic Centre of Excellence in Disease Genetics
- Novo Nordisk Foundation
- Nuffield Department of Medicine (NDM)
- Ollqvist Foundation
- Orion-Farmos Research Foundation
- Oxford Biomedical Research Centre
- Paavo Nurmi Foundation
- Pahlssons Foundation
- Paivikki and Sakari Sohlberg Foundation
- Perklen Foundation
- Samfundet Folkhalsan
- Signe and Ane Gyllenberg Foundation
- Sigrid Juselius Foundation
- Singapore National Research Foundation
- Social Insurance Institution of Finland
- South-Eastern Norway Regional Health Authority [2011060]
- Swedish Cultural Foundation in Finland
- Swedish Heart-Lung Foundation
- Swedish Research Council
- American Federation for Aging Research
- Einstein Glenn Center
- Canadian province of Newfoundland
- Canadian province of Labrador
- Canadian province of Nova Scotia
- Canadian province of New Brunswick
- Skane Regional Health Authority
- Tekes Finnish Funding Agency for Innovation [1510/31/06]
- Timber Merchant Vilhelm Bang's Foundation
- Turku University Foundation
- UK National Institute for Health Research [RP-PG-0407-10371]
- Uppsala University
- Uppsala University Hospital
- Wellcome Trust [064890, 083948, 085475, 086596, 090367, 090532/Z/09/Z, 092447, 095101/Z/10/Z, 200837/Z/16/Z, 095552, 098017, 098381, 098051, 084723, 072960/2/03/2, 086113/Z/08/Z]
- Lundbeck Foundation [R190-2014-3904] Funding Source: researchfish
- Medical Research Council [G0700931, MC_PC_13040, MR/L01341X/1, MC_UU_12015/1, MC_PC_13048, MR/K007017/1, MR/K002414/1, G0601966, MR/M501633/1, G0601261, MR/M501633/2, MC_UU_12015/2] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10099, NF-SI-0611-10219, RP-PG-0407-10371, NF-SI-0512-10135, NF-SI-0616-10080, NF-SI-0611-10136, NF-SI-0513-10109] Funding Source: researchfish
- NNF Center for Basic Metabolic Research [Grarup Group, Pers Group] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0005339, NNF16OC0021496, NNF14OC0009819] Funding Source: researchfish
- Steno Diabetes Center Copenhagen (SDCC) [SDCC 3.A Complications] Funding Source: researchfish
- Wellcome Trust [098395/Z/12/Z] Funding Source: researchfish
- Korea Health Promotion Institute [2012-N73002-00] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Institutes of Health Research (NIHR) [RP-PG-0407-10371] Funding Source: National Institutes of Health Research (NIHR)
- MRC [MR/M501633/2, MR/K007017/1, MR/M501633/1, MR/K002414/1, MC_UU_12015/2, MR/L01341X/1, G0700931, G0601966, MC_UU_12015/1, G0601261] Funding Source: UKRI
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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) in AKT2 and 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 in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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