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Cited by 423Genetic Associations and EpidemiologyDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes and associated disorders

The DOI matches its Crossref record; 28 of the 29 references it cites were found in a registry or an index.

A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes

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Moltke, Ida, Grarup, Niels, Jørgensen, Marit E., Bjerregaard, Peter, Treebak, Jonas T., Fumagalli, Matteo, Korneliussen, Thorfinn S., Andersen, Marianne A., Nielsen, Thomas S., Krarup, Nikolaj T., Gjesing, Anette P., Zierath, Juleen R., Linneberg, Allan, Wu, Xueli, Sun, Guangqing, Jin, Xin, Al-Aama, Jumana, Wang, Jun, Borch-Johnsen, Knut, Pedersen, Oluf, Nielsen, Rasmus, Albrechtsen, Anders, Hansen, Torben·2014·Nature
DOI 10.1038/nature13425
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Abstract

The Greenlandic population, a small and historically isolated founder population comprising about 57,000 inhabitants, has experienced a dramatic increase in type 2 diabetes (T2D) prevalence during the past 25 years. Motivated by this, we performed association mapping of T2D-related quantitative traits in up to 2,575 Greenlandic individuals without known diabetes. Using array-based genotyping and exome sequencing, we discovered a nonsense p.Arg684Ter variant (in which arginine is replaced by a termination codon) in the gene TBC1D4 with an allele frequency of 17%. Here we show that homozygous carriers of this variant have markedly higher concentrations of plasma glucose (β = 3.8 mmol l(-1), P = 2.5 × 10(-35)) and serum insulin (β = 165 pmol l(-1), P = 1.5 × 10(-20)) 2 hours after an oral glucose load compared with individuals with other genotypes (both non-carriers and heterozygous carriers). Furthermore, homozygous carriers have marginally lower concentrations of fasting plasma glucose (β = -0.18 mmol l(-1), P = 1.1 × 10(-6)) and fasting serum insulin (β = -8.3 pmol l(-1), P = 0.0014), and their T2D risk is markedly increased (odds ratio (OR) = 10.3, P = 1.6 × 10(-24)). Heterozygous carriers have a moderately higher plasma glucose concentration 2 hours after an oral glucose load than non-carriers (β = 0.43 mmol l(-1), P = 5.3 × 10(-5)). Analyses of skeletal muscle biopsies showed lower messenger RNA and protein levels of the long isoform of TBC1D4, and lower muscle protein levels of the glucose transporter GLUT4, with increasing number of p.Arg684Ter alleles. These findings are concomitant with a severely decreased insulin-stimulated glucose uptake in muscle, leading to postprandial hyperglycaemia, impaired glucose tolerance and T2D. The observed effect sizes are several times larger than any previous findings in large-scale genome-wide association studies of these traits and constitute further proof of the value of conducting genetic association studies outside the traditional setting of large homogeneous populations.

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Authors
Moltke, I., Grarup, N., Jørgensen, M. E., Bjerregaard, P., Treebak, J. T., Fumagalli, M., Korneliussen, T. S., Andersen, M. A., Nielsen, T. S., Krarup, N. T., Gjesing, A. P., Zierath, J. R., Linneberg, A., Wu, X., Sun, G., Jin, X., Al-Aama, J., Wang, J., Borch-Johnsen, K., Pedersen, O., Nielsen, R., Albrechtsen, A., & Hansen, T.
Affiliations
  • University of Copenhagen (DK)
  • University of Southern Denmark (DK)
  • University of California, Berkeley (US)
  • Glostrup Hospital (DK)
  • BGI Group (China) (CN)
  • Macau University of Science and Technology (MO)
Corresponding author
  • Albrechtsen, Anders
  • Hansen, Torben
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2014-06-18
Volume
512
Issue
7513
Pages
190-193
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature13425
OpenAlex
W1991241396
Cited by
418
References
29
Citations by year
2026: 19 · 2025: 30 · 2024: 38 · 2023: 32 · 2022: 30 · 2021: 38 · 2020: 29 · 2019: 41 · 2018: 43 · 2017: 36 · 2016: 48 · 2015: 27 · 2014: 7
FWCI
25.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Villum Fonden (00007171)
  • Novo Nordisk Fonden
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
TBC1D4, type 2 diabetes, muscle insulin resistance, nonsense mutation, founder populations, plasma glucose, serum insulin, oral glucose tolerance, genetic association, insulin signaling
MeSH terms
Adult, Blood Glucose, Diabetes Mellitus, Type 2, Gene Frequency, Genotype, Greenland, Humans, Insulin, Insulin Resistance, Middle Aged, Genetic Variation, Codon, Nonsense, Muscle, Skeletal, GTPase-Activating Proteins, Genome-Wide Association Study

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