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  • Review Article
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Pharmacogenomics in diabetes mellitus: insights into drug action and drug discovery

Key Points

  • The list of known variants affecting type 2 diabetes mellitus (T2DM) risk confirms that this disease has a multifactorial aetiology

  • The concept of precision medicine has been exemplified in pharmacogenetic studies of monogenic diabetes mellitus

  • The genetic architecture of mild adverse drug reactions and treatment efficacy for antidiabetic agents probably resembles that of T2DM and other complex traits

  • Existing pharmacogenetic evidence of T2DM is limited; future pharmacogenomic studies utilizing large samples sizes will help identify variants that reveal novel mechanisms of drug action

  • Genetic evidence-based 'dose-response' curves have been used in validating candidate drug targets

  • Pharmacogenomic studies adopting a systems biology approach are expected to provide context specific evidence for future T2DM drug development

Abstract

Genomic studies have greatly advanced our understanding of the multifactorial aetiology of type 2 diabetes mellitus (T2DM) as well as the multiple subtypes of monogenic diabetes mellitus. In this Review, we discuss the existing pharmacogenetic evidence in both monogenic diabetes mellitus and T2DM. We highlight mechanistic insights from the study of adverse effects and the efficacy of antidiabetic drugs. The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A represents a clear example of how pharmacogenetics can direct patient care. However, pharmacogenomic studies of response to antidiabetic drugs in T2DM has yet to be translated into clinical practice, although some moderate genetic effects have now been described that merit follow-up in trials in which patients are selected according to genotype. We also discuss how future pharmacogenomic findings could provide insights into treatment response in diabetes mellitus that, in addition to other areas of human genetics, facilitates drug discovery and drug development for T2DM.

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Figure 1: Target organs and action mechanism of antidiabetic drugs.
Figure 2: Dose-response curve for the therapeutic hypothesis of selective SGLT-2 inhibitors.

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Acknowledgements

E.R.P. holds a Wellcome Trust New Investigator Award 102820/Z/13/Z.

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Correspondence to Ewan R. Pearson.

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Zhou, K., Pedersen, H., Dawed, A. et al. Pharmacogenomics in diabetes mellitus: insights into drug action and drug discovery. Nat Rev Endocrinol 12, 337–346 (2016). https://doi.org/10.1038/nrendo.2016.51

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