Pharmacogenetic studies update in type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment.

Keywords: Genetic variants; Oral antidiabetic drugs; Personalized medicine; Pharmacogenetics; Type 2 diabetes mellitus.

Figure 1

Effects of gene polymorphisms on drug efficacy and toxicity.

Figure 2

Schematic representation of cellular locations of metformin transporters. SLC22A3: Solute carrier family 22 member 3; SLC29A4: Solute carrier family 29 member 4.

Figure 3

Schematic diagram showing the Kir6.2 and SUR1 variants affecting sulfonylurea efficacy. Pancreatic β cell membrane with SUR1/Kir6.2 variant leads to improper closing of KATP channel on binding with SUs. This subsequently leads to poor membrane depolarization and less influx of Ca²⁺ ions which will result in less and delayed insulin secretion. Hence, low level of insulin molecules will be available to bind with IRS1 and lead to an impaired signaling cascade resulting in poor management of glycemic condition. SUs: Sulfonylureas; SUR1: Sulfonylurea receptor 1; KATP: ATP-sensitive potassium channel; IRS1: Insulin receptor substrate 1; SUR 1: Sulfonylurea Receptor 1.

Figure 4

Schematic representations of peroxisome prolierator-activated receptor γ variants affecting the efficacy of thiazolidinediones. TZDs: Thiazolidinediones; PPARγ: Peroxisome proliferator-activated receptor γ.

Figure 5

Clinical applications of pharmacogenetics in type 2 diabetes mellitus. T2DM: Type 2 diabetes mellitus; HbA1c: Glycated haemoglobin.