Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Abstract

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6×10−14) greater metformin-induced in haemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 is the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

10 Years of GWAS Discovery: Biology, Function, and Translation

“…Examples from T2D research highlight the diverse routes by which human genetics can inform translational medicine: (1) the combination of common-variant GWASs and candidate-gene resequencing has demonstrated that loss-of-function mutations in SLC30A8 (MIM: 611145; encoding a zinc transporter expressed in pancreatic islets) are protective for T2D, leading to efforts by several pharma companies to develop ZnT-8 antagonists; 93 (2) the use of genetic variants as instruments that ''simulate'' variation in environmental and biochemical exposures has clarified the extent to which vitamin D intake, early nutrition, circulating lipid levels, and chronic inflammation play causal roles with respect to the development of T2D [94][95][96][97][98] and has defined the relationship between insulin resistance and the distribution of adipose tissue; 99 (3) the identification of genetic variants associated with individual variation in response to commonly used therapeutic agents has refined our understanding of the mechanisms through which those agents operate 100,101 and, in some instances, has led to therapeutic optimization on the basis of genetic and/or clinical phenotype; 102 and (4) the combination of -omic measurements, longitudinal clinical phenotypes, and GWAS data has highlighted sets of molecules (e.g., branched-chain amino acids) that not only are prospectively associated with T2D progression but could also play a causal role in T2D development and thereby provide valuable clinical tools for stratification and prognostication. 103,104 Auto-immune Diseases Variant and Gene Discovery.…”

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

“…(SLC2A2) has a significant impact on metformin response 19 . That is, genetic polymorphisms of SLC2A2 were associated at genomewide level significance with glycemic response to the drug in 8,000 patients with T2D.…”

Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome

“…Polymorphisms in genes involved in metformin transport or action have been implicated in the heterogeneous response to metformin in type 2 diabetes [21,22] and, to a lesser extent, in PCOS [23][24][25][26][27]. In a prospective randomised trial of over 300 women with PCOS, a polymorphism in the STK11 gene (expressed in the liver, also known as LKB1), a serine threonine kinase that is required for metformin efficacy, was shown to be associated with a poor ovulatory response to metformin [26].…”

“…In a prospective randomised trial of over 300 women with PCOS, a polymorphism in the STK11 gene (expressed in the liver, also known as LKB1), a serine threonine kinase that is required for metformin efficacy, was shown to be associated with a poor ovulatory response to metformin [26]. In type 2 diabetes, polymorphisms in the ATM gene, which regulates the activity of AMP-activated protein kinase (AMPK), a protein that plays a key role in cellular energy homeostasis [21], and in genes encoding metformin transport proteins, such as OCT1, which is involved in the transport of metformin into hepatocytes [28], and OCT2, which is involved in elimination of metformin through the renal tubule cells, are thought to play a role in metformin response. Similarly, in a study of 675 women with PCOS, 29.8% had non-functional alleles and 57.9% had low-functional alleles for polymorphisms in eight common SNPs on OCT1, OCT2 and ATM genes [24].…”