Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes
Open accessAbstract
Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.
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A Mendelian randomization study did not provide evidence for a causal role of glycine in diabetes-related traits.
“A Mendelian randomization study, however, did not provide evidence for a causal role of glycine in diabetes-related traits (42).”
From Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes (2015) · cites this paper as [42]
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- Authors
- Xie, W., Wood, A. R., Lyssenko, V., Weedon, M. N., Knowles, J. W., Alkayyali, S., Assimes, T. L., Quertermous, T., Abbasi, F., Paananen, J., Häring, H., Hansen, T., Pedersen, O., Smith, U., Laakso, M., the MAGIC Investigators, the DIAGRAM Consortium, the GENESIS Consortium, the RISC Consortium, Dekker, J. M., Nolan, J. J., Groop, L., Ferrannini, E., Adam, K.-P., Gall, W. E., Frayling, T. M., & Walker, M.
- Affiliations
- University of Exeter (GB)
- Lund University (SE)
- Stanford Medicine (US)
- University of Eastern Finland (FI)
- University of Tübingen (DE)
- University of Copenhagen (DK)
- University of Gothenburg (SE)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University of Pisa (IT)
- Metabolon (United States) (US)
- Newcastle University (GB)
- Corresponding author
- Frayling, Timothy M.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-05-17
- Volume
- 62
- Issue
- 6
- Pages
- 2141-2150
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3661655
- OpenAlex
- W2146510798
- Cited by
- 83
- References
- 54
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 5 · 2020: 5 · 2019: 10 · 2018: 10 · 2017: 5 · 2016: 11 · 2015: 7 · 2014: 7 · 2013: 1
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust (083270/Z/07/Z)
- National Institute for Health and Care Research (NF-SI-0510-10150)
- Medical Research Council (G0601261)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- glycine metabolism, insulin sensitivity, type 2 diabetes, genetic variants, glycine synthesis, serine metabolism, betaine metabolism, glutathione metabolism, CPS1, PHGDH, BHMT, ALDH1L1, circulating metabolites, biomarkers, hyperinsulinemic-euglycemic clamp
- MeSH terms
- Adult, Betaine, Diabetes Mellitus, Type 2, Female, Glycine, Humans, Insulin Resistance, Male, Middle Aged, Serine
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