Pharmacogenomics in diabetes mellitus: insights into drug action and drug discovery

Journal name:
Nature Reviews Endocrinology
Volume:
12,
Pages:
337–346
Year published:
DOI:
doi:10.1038/nrendo.2016.51
Published online

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.

At a glance

Figures

  1. Target organs and action mechanism of antidiabetic drugs.
    Figure 1: Target organs and action mechanism of antidiabetic drugs.

    The mechanism for metformin action remains uncertain: metformin might target the liver to reduce gluconeogenesis and skeletal muscles to enhance peripheral glucose utilization110, with a possible role in the gut to increase levels of glucagon-like peptide 1 (GLP-1) (Ref. 111). Sulfonylureas and meglitinides increase insulin secretion in the pancreas112, 113. Thiazolidinediones (TZDs) act as insulin sensitizers in skeletal muscle, adipose tissue and the liver114. GLP-1 receptor (GLP-1R) agonists (GLP-1RA) target the pancreas to increase insulin secretion and reduce glucagon production, as well as act in the gut to reduce gastric emptying115. Dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4i) increase endogenous incretin levels by blocking the action of DPP-4 (Ref. 115). Sodium–glucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2i) reduce renal glucose reabsorption116.

  2. Dose-response curve for the therapeutic hypothesis of selective SGLT-2 inhibitors.
    Figure 2: Dose-response curve for the therapeutic hypothesis of selective SGLT-2 inhibitors.

    The y axis represents a range of glucose levels, in which the high range represents the hyperglycaemic state observed in type 2 diabetes mellitus as compared to the normal range observed in healthy individuals or those patients with familial renal glycosuria. The x axis represents a spectrum of naturally occurring sodium–glucose cotransporter 2 (SGLT-2) loss-of-function variants observed in patients with familial renal glycosuria. The variants were ordered from the mild heterozygotes to severe homozygotes as defined by the resulting severity of glycosuria. For on-target adverse reactions, the benign glucosuria and apparently normal health observed in these patients supports the safety profile of selectively inhibiting SGLT-2 function in a wide dose window.

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Affiliations

  1. School of Medicine, University of Dundee, Dundee, DD1 9SY, UK.

    • Kaixin Zhou,
    • Adem Y. Dawed &
    • Ewan R. Pearson
  2. Department of Systems Biology, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.

    • Helle Krogh Pedersen

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All authors contributed to all aspects of the manuscript.

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The authors declare no competing interests.

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  • Kaixin Zhou

    Kaixin Zhou is a lecturer at the School of Medicine, University of Dundee, UK. Before this appointment, he was a Sir Henry Wellcome Fellow holding academic positions at the University of Dundee, University of Oxford, UK, and University of Hong Kong, China. His current research interests include using large-scale genomic data linked to electronic medical records, and pharmaco-epidemiological approach to understand the biological mechanisms of drug action, drug–drug interactions, adverse drug reactions, and their relevance to stratified medicine.

  • Helle Krogh Pedersen

    Helle Krogh Pedersen is a Postdoctoral research fellow at the department of Systems Biology, Technical University of Denmark, in Lyngby, Denmark. Her research focuses on multi-level systems biology approaches for integrating heterogeneous data sources in the context of diabetes mellitus.

  • Adem Y. Dawed

    Adem Y. Dawed received his Master's Degree in Public health from Lund University, Sweden in 2014. He is currently a PhD student at the division of Cardiovascular and Diabetes Medicine, University of Dundee, UK. His research focuses on investigating clinical and genetic determinants of drug response in type 2 diabetes mellitus.

  • Ewan R. Pearson

    Ewan R. Pearson is a Professor in Diabetic Medicine and an Honorary Consultant in Diabetes and Endocrinology at the University of Dundee, UK. He holds a New Investigator Award from the Wellcome Trust to investigate determinants of drug response in diabetes mellitus and is the academic lead on the IMI-DIRECT project. His research interests include phenotypic and genotypic determinants of drug responses, the aetiology of young-onset diabetes mellitus and the mechanisms driving progression of this disease.

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