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Diabetes

Dynamic measures of insulin action identify genetic determinants of dysglycemia

Nature Genetics volume 55, pages 905–907 (2023)Cite this article

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Genome-wide association studies (GWAS) of type 2 diabetes have identified few loci connected to muscle biology. A GWAS of post-glucose-challenge measures of insulin has now identified loci related to insulin resistance and GLUT4 regulation in skeletal muscle, illustrating the benefit of studying dynamic glycemic measures.

Focusing on two well-established glycemic measures derived from oral glucose tolerance testing (OGTT) to approximate postprandial insulin resistance, the authors calculated (i) the insulin fold change (IFC) between the 2-hour and fasting insulin measures and (ii) the modified Stumvoll insulin sensitivity index (ISI) equation, which incorporates fasting and 2-hour insulin as well as 2-hour glucose measures and was developed as a proxy for the gold standard hyperinsulinemic–euglycemic clamp measure of insulin sensitivity5. They performed GWAS for each glycemic measure adjusted for body-mass index in >53,000 individuals of European ancestry without a diagnosis of diabetes and identified a total of 11 loci (Fig. 1b), including BCL2, NYAP2 and IRSI, that had previously been identified in a smaller study of ISI (N = 16,753) by Walford et al.6. Of these 11 loci, 10 demonstrated substantial support for a shared genetic signal with T2D from statistical colocalization as well as lead variant associations with T2D. An additional locus, BICC1, was identified in a combined analysis of 1,837 individuals of Hispanic American and East Asian ancestry, though it was not replicated in the European subset or full-cohort analysis.

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Fig. 1: GWAS of measures of insulin action following glucose challenge identify loci related to insulin resistance, including SLC2A4.

References

  1. James, D. E., Stockli, J. & Birnbaum, M. J. Nat. Rev. Mol. Cell Biol. 22, 751–771 (2021).

    Article  CAS  PubMed  Google Scholar 

  2. Scott, L. J. et al. Nat. Commun. 7, 11764 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sharabi, K., Tavares, C. D., Rines, A. K. & Puigserver, P. Mol. Aspects Med. 46, 21–33 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Williamson, A. Nat. Genet. https://doi.org/10.1038/s41588-023-01408-9 (2023).

  5. Stumvoll, M., Van Haeften, T., Fritsche, A. & Gerich, J. Diabetes Care 24, 796–797 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Walford, G. A. et al. Diabetes 65, 3200–3211 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Klip, A., McGraw, T. E. & James, D. E. J. Biol. Chem. 294, 11369–11381 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen, J. et al. Nat. Genet. 53, 840–860 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gonzalez, A. et al. Diabet. Med. 37, 689–696 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Moltke, I. et al. Nature 512, 190–193 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Udler, M. S. et al. PLoS Med. 15, e1002654 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kim, H. et al. Diabetologia 66, 495–507 (2022).

    Article  PubMed  Google Scholar 

  13. Ahlqvist, E. et al. Lancet Diabetes Endocrinol. 6, 361–369 (2018).

    Article  PubMed  Google Scholar 

  14. DiCorpo, D. et al. Diabetes Care 45, 674–683 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Reaven, G. Arterioscler. Thromb. Vasc. Biol. 32, 1754–1759 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

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Authors and Affiliations

  1. Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Miriam S. Udler

  2. Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Miriam S. Udler

  3. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Miriam S. Udler

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Correspondence to Miriam S. Udler.

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Udler, M.S. Dynamic measures of insulin action identify genetic determinants of dysglycemia. Nat Genet 55, 905–907 (2023). https://doi.org/10.1038/s41588-023-01346-6

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