Pharmacogenomics in type 2 diabetes mellitus and metabolic disorders

Abstract

Pharmacogenomics, a newly growing branch of medicine, makes use of an individual’s genetic information to guide therapy and has become an important tool in achieving ‘personalised medicine’. The discovery of novel genetic polymorphisms in drug transporters, targets and metab0060046lising enzymes has given an insight into the biological phenomena of drug efficacy and toxicity. Type 2 diabetes mellitus has been on the rise in both developed and developing countries owing to increase in life span as well as change in lifestyle. The advances in the field of pharmacogenomics has revealed diverse issues associated with onset of type 2 diabetes and genetic variants associated with varied responses to commonly prescribed antidiabetic drugs. Genetic polymorphisms like A1369 variant increasing MgATPase activity of KATPchannel have been found to provide a plausible molecular mechanism by which the K23/A1369 haplotype increases susceptibility to type 2 diabetes in humans homozygous for these variants. The oral hypoglycaemic drugs sulfonylureas act through KATPchannel blockade resulting in stimulation of insulin release from pancreatic β-cells and have been a basis of type 2 diabetes pharma-cotherapy since long time. However, sulfonylureas have been found to have interindividual variability in drug response and adverse effects. Interindividual variations in efficacy and adverse events are also recognised with metformin, a biguanide which improves insulin resistance in type 2 diabetes. Genetic polymorphisms in OCT1 and OCT2, two organic cation transporters, have been found to be associated with changes in responses to metformin. Similarly, the regulatory and glucose homeostasis-related single nucleotide polymorphisms (SNPs) in peroxisome proliferator-activated receptor (PPAR) agonist-modulated genes can be used to explain the interindividual variability in response to thiazolidinediones. In addition, the identifi cation of genetic defects responsible for inherited metabolic disorders like phenylketonuria, urea cycle disorder and Niemann–Pick disease has opened a promising approach to promote drug development in enzyme-deficient diseases. The detection of association of Niemann–Pick disease, type C1, gene-like 1 (NPC1L1) variation with response to ezetimibe, a cholesterol uptake inhibitor, has confirmed the role of pharmacogenomics in drug therapy of metabolic disorders. Hence, this chapter will discuss in detail the application of pharmacogenomics in drug response pertaining to type 2 diabetes mellitus and other metabolic disorders.