Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3)

Liang, Xiaomin; Chien, Huan‐Chieh; Yee, Sook Wah; Giacomini, Marilyn M.; Chen, Eugene C.; Piao, Meiling; Jia, Hao; Twelves, Jolyn; Lepist, Eve-Irene; Ray, Adrian S.; Giacomini, Kathleen M.

doi:10.1021/acs.molpharmaceut.5b00501

Cited by 93 publications

(94 citation statements)

References 39 publications

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“…Growth differentiation factor 15 ( GDF15 ) was the top upregulated AMPK-independent gene (Fig 2B) and its overexpression is known to result in improved insulin sensitivity [50]. The transporter solute carrier family 19, member 3 ( SLC19A3 ) was also an upregulated AMPK-dependent gene (S1 Table), and is known to play a role in the intestinal absorption and tissue distribution of metformin [51]. These findings further support that metformin induces protein coding genes which play a role in cancer and T2D.…”

Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Metformin Hepatic Response

et al. 2016

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Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.

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Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Metformin Hepatic Response

et al. 2016

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“…The transcript levels of SLC2A2 were determined using TaqMan probe (ID Hs01096908_m1). The relative expression level of SLC2A2 transcript was calculated by the comparative method (ΔΔCt) normalized to the housekeeping gene GAPDH, as described previously52.…”

Section: Methodsmentioning

confidence: 99%

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

Yee²,

et al. 2016

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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.

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“…This led to the discovery that the antibiotic trimethoprim also potently inhibits thiamine uptake [272]. Metformin is also both a substrate and an inhibitor of one of the transporters [275].…”

Section: Figure 5 Unsupervised and Supervised Learning Methods In Chmentioning

confidence: 99%

Control of metabolite efflux in microbial cell factories: current advances and future prospects

Kell¹

2018

Preprint

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The yield and ease of purification of biotechnological products are typically greatly enhanced if they can be secreted into the external medium. Although not universally appreciated, however, small molecule biotechnological products do not ‘float across’ the phospholipid bilayer portion of biological membranes, and thus they need transporters to assist their passage into the extramembrane and extracellular spaces. Some of these transporters may be reversible, equilibrative transporters that might more normally be used for uptake, while others may have an efflux directionality imposed on them via suitable energy coupling mechanisms. Despite the energetic costs of small molecule synthesis, natural evolution does in fact provide a number of mechanisms by which the secretion of such products can actually enhance fitness. Where available these provide useful starting points, and assaying for such activities is crucial. In particular, in a systems biology approach, we first need to identify such/suitable activities before we can seek to increase them. They may then be improved through promoter engineering, via manipulation of control elements, or by directed evolution of the transporter proteins themselves. Modern methods of synthetic biology provide enormous opportunities for all kinds of efflux transporter engineering; they are just beginning to be realised.

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Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3)

Cited by 93 publications

References 39 publications

Genomic Characterization of Metformin Hepatic Response

Genomic Characterization of Metformin Hepatic Response

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

Control of metabolite efflux in microbial cell factories: current advances and future prospects

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