A Low-Frequency Inactivating Akt2 Variant Enriched in the Finnish Population is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.
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Accepted version
Supporting information
Author(s)
Type
Journal Article
Abstract
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 insulin, 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 fasting plasma insulin (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-hour 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.
Date Issued
2017-03-24
Date Acceptance
2017-03-13
ISSN
0012-1797
Publisher
American Diabetes Association
Start Page
2019
End Page
2032
Journal / Book Title
Diabetes
Volume
66
Issue
7
Copyright Statement
© 2017 the American Diabetes Association. http://www.diabetesjournals.org/content/license
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
Sponsor
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
National Institute for Health Research
Public Health England
Identifier
db16-1329
Grant Number
NF-SI-0611-10136
RDC01 79560
MR/L01341X/1
RTJ6219303-1
6509268
Subjects
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
BETA-CELL MASS
NEUROTROPHIC FACTOR
GDNF FAMILY
GLUCOSE-HOMEOSTASIS
FATTY RAT
ZDF RATS
EXPRESSION
SECRETION
NEURTURIN
MELLITUS
African Americans
Alleles
Asian Continental Ancestry Group
Case-Control Studies
Diabetes Mellitus, Type 2
European Continental Ancestry Group
Fasting
Finland
Gene Frequency
Genetic Predisposition to Disease
Genotype
Hispanic Americans
Humans
Insulin
Insulin Resistance
Odds Ratio
Proto-Oncogene Proteins c-akt
11 Medical And Health Sciences
Publication Status
Published