Pharmacogenetics of metformin response: a step in the path toward personalized medicine

Abstract

Type 2 diabetes mellitus affects 9.6% of the adults in the United States and more than 200 million people worldwide. Diabetes can be a devastating disease, but it can now be treated with nine classes of approved drugs (insulins, sulfonylureas, glinides, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, glucagon-like peptide 1 mimetics, amylin mimetics, and dipeptidyl peptidase 4 inhibitors), in addition to diet and exercise regimens. Choosing which drug to give a patient is based on efficacy and also availability, cost, safety, tolerability, and convenience. Personalized medicine promises a path for individually optimized treatment choices, but realizing this promise will require a more comprehensive characterization of disease and drug response. In this issue of the JCI, Shu et al. make significant progress by integrating diverse data supporting the hypothesis that genetic variation in organic cation transporter 1 (OCT1) affects the response to the widely used biguanide metformin (see the related article beginning on page 1422). We discuss metformin, OCT1, pharmacogenetics, and how the integrative genomics revolution is likely to change our understanding and treatment of diabetes.

Figure 1. Elucidating the complexity of drug response.

(A) A classical pharmacogenetic approach to identifying genes associated with drug response involves testing DNA variations in candidate genes for association to drug response. Variations in cytochrome P450s and drug targets such as VKORC1 (target of warfarin) have been identified that explain variation in drug response. Individual genotypes corresponding to such variations can be used to distinguish responders from nonresponders or rapid from slow metabolizers or those at risk of adverse events. (B) Pharmacogenomic studies involve larger-scale genome-wide association approaches or the integration of a diversity of genetic, functional genomic, and other data to elucidate the complexity of drug response. In this issue of the JCI, Shu et al. (4) employed cell-based experiments, in vivo studies in mice, and in vivo human trials to identify OCT1 as a gene associated with response to treatment with metformin. The use of multiple experimental approaches provided more convincing results than could a single genetic study in implicating OCT1 as a metformin response gene.