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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Williamson, A. ; Hatem, G. LU ; Aly, D.M. LU ; Ahlqvist, E. LU ; Prasad, R.B. LU ; Groop, L. LU ; Meigs, J.B. and Langenberg, C. (2023) In Nature Genetics 55(6). p.973-983
Abstract
Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the... (More)
Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc. (Less)
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type
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published
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keywords
Blood Glucose, Diabetes Mellitus, Type 2, Genome-Wide Association Study, Glucose, Humans, Insulin, Insulin Resistance, glucose, glucose transporter 4, insulin, adipocyte, ancestry group, Article, body mass, cell culture, controlled study, gene expression, gene identification, genetic variability, genome-wide association study, glucose transport, human, insulin level, insulin resistance, meta analysis (topic), non insulin dependent diabetes mellitus, transcription regulation, genetics, glucose blood level, metabolism
in
Nature Genetics
volume
55
issue
6
pages
11 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85161434094
ISSN
1061-4036
DOI
10.1038/s41588-023-01408-9
language
English
LU publication?
yes
id
6adcc06f-a8d0-4413-9604-f244c2628fdc
date added to LUP
2023-11-14 16:08:52
date last changed
2024-04-12 06:16:18
@article{6adcc06f-a8d0-4413-9604-f244c2628fdc,
  abstract     = {{Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in &gt;55,000 participants from three ancestry groups. We identified ten new loci (P &lt; 5 × 10−8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.}},
  author       = {{Williamson, A. and Hatem, G. and Aly, D.M. and Ahlqvist, E. and Prasad, R.B. and Groop, L. and Meigs, J.B. and Langenberg, C.}},
  issn         = {{1061-4036}},
  keywords     = {{Blood Glucose; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Glucose; Humans; Insulin; Insulin Resistance; glucose; glucose transporter 4; insulin; adipocyte; ancestry group; Article; body mass; cell culture; controlled study; gene expression; gene identification; genetic variability; genome-wide association study; glucose transport; human; insulin level; insulin resistance; meta analysis (topic); non insulin dependent diabetes mellitus; transcription regulation; genetics; glucose blood level; metabolism}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{973--983}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake}},
  url          = {{http://dx.doi.org/10.1038/s41588-023-01408-9}},
  doi          = {{10.1038/s41588-023-01408-9}},
  volume       = {{55}},
  year         = {{2023}},
}