Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response
Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers....
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| creator | Ustinova, Monta Ansone, Laura Silamikelis, Ivars Rovite, Vita Elbere, Ilze Silamikele, Laila Kalnina, Ineta Fridmanis, Davids Sokolovska, Jelizaveta Konrade, Ilze Pirags, Valdis Klovins, Janis |
| description | Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c [greater than or equal to] 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log.sub.2 FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus. |
| doi_str_mv | 10.1371/journal.pone.0237400 |
| format | Article |
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Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c [greater than or equal to] 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log.sub.2 FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0237400</identifier><identifier>PMID: 32780768</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Analysis ; Antidiabetics ; Biological markers ; Biology and Life Sciences ; Biomarkers ; Biomedical research ; Blood ; Breast cancer ; CCR2 protein ; CD14 antigen ; CD163 antigen ; Cell division ; Cholesterol ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Drug therapy ; Electron transport chain ; Endocrinology ; Ethics ; Gastrointestinal cancer ; Gene expression ; Genes ; Genomes ; Glucose ; Homeostasis ; Human rights ; Hyperglycemia ; Immune response ; Insulin resistance ; IRS-2 gene ; Kinases ; Medicine ; Medicine and Health Sciences ; Metformin ; Mitochondria ; Monocyte chemoattractant protein 1 ; Patients ; Physiological aspects ; Research and analysis methods ; Ribonucleic acid ; RNA ; RNA sequencing ; Stem cells ; Studies ; Testing ; Transcriptomics ; Type 2 diabetes</subject><ispartof>PloS one, 2020-08, Vol.15 (8), p.e0237400-e0237400</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Ustinova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Ustinova et al 2020 Ustinova et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c669t-340e07db65e51ee814dd473378a0286e5b9dec6f3c73184cf337359742d8e0cb3</citedby><cites>FETCH-LOGICAL-c669t-340e07db65e51ee814dd473378a0286e5b9dec6f3c73184cf337359742d8e0cb3</cites><orcidid>0000-0001-8362-5505</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418999/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418999/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids></links><search><creatorcontrib>Ustinova, Monta</creatorcontrib><creatorcontrib>Ansone, Laura</creatorcontrib><creatorcontrib>Silamikelis, Ivars</creatorcontrib><creatorcontrib>Rovite, Vita</creatorcontrib><creatorcontrib>Elbere, Ilze</creatorcontrib><creatorcontrib>Silamikele, Laila</creatorcontrib><creatorcontrib>Kalnina, Ineta</creatorcontrib><creatorcontrib>Fridmanis, Davids</creatorcontrib><creatorcontrib>Sokolovska, Jelizaveta</creatorcontrib><creatorcontrib>Konrade, Ilze</creatorcontrib><creatorcontrib>Pirags, Valdis</creatorcontrib><creatorcontrib>Klovins, Janis</creatorcontrib><title>Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response</title><title>PloS one</title><description>Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. 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Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.</description><subject>Analysis</subject><subject>Antidiabetics</subject><subject>Biological markers</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Biomedical research</subject><subject>Blood</subject><subject>Breast cancer</subject><subject>CCR2 protein</subject><subject>CD14 antigen</subject><subject>CD163 antigen</subject><subject>Cell division</subject><subject>Cholesterol</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Drug therapy</subject><subject>Electron transport chain</subject><subject>Endocrinology</subject><subject>Ethics</subject><subject>Gastrointestinal cancer</subject><subject>Gene 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transcriptome profiling reveals signatures of metformin and its therapeutic response</title><author>Ustinova, Monta ; Ansone, Laura ; Silamikelis, Ivars ; Rovite, Vita ; Elbere, Ilze ; Silamikele, Laila ; Kalnina, Ineta ; Fridmanis, Davids ; Sokolovska, Jelizaveta ; Konrade, Ilze ; Pirags, Valdis ; Klovins, Janis</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c669t-340e07db65e51ee814dd473378a0286e5b9dec6f3c73184cf337359742d8e0cb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Analysis</topic><topic>Antidiabetics</topic><topic>Biological markers</topic><topic>Biology and Life Sciences</topic><topic>Biomarkers</topic><topic>Biomedical research</topic><topic>Blood</topic><topic>Breast cancer</topic><topic>CCR2 protein</topic><topic>CD14 antigen</topic><topic>CD163 antigen</topic><topic>Cell division</topic><topic>Cholesterol</topic><topic>Diabetes</topic><topic>Diabetes 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type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers. We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve volunteers with type 2 diabetes in vivo. The longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B), and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time a transcriptome-based molecular discrimination between metformin responders (delta HbA1c [greater than or equal to] 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol), that is determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug. Moreover, we found a significant upregulation of IRS2 gene (log.sub.2 FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metformin in patients with type 2 diabetes mellitus.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>32780768</pmid><doi>10.1371/journal.pone.0237400</doi><orcidid>https://orcid.org/0000-0001-8362-5505</orcidid><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
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| source | DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Analysis Antidiabetics Biological markers Biology and Life Sciences Biomarkers Biomedical research Blood Breast cancer CCR2 protein CD14 antigen CD163 antigen Cell division Cholesterol Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Drug therapy Electron transport chain Endocrinology Ethics Gastrointestinal cancer Gene expression Genes Genomes Glucose Homeostasis Human rights Hyperglycemia Immune response Insulin resistance IRS-2 gene Kinases Medicine Medicine and Health Sciences Metformin Mitochondria Monocyte chemoattractant protein 1 Patients Physiological aspects Research and analysis methods Ribonucleic acid RNA RNA sequencing Stem cells Studies Testing Transcriptomics Type 2 diabetes |
| title | Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T20%3A37%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Whole-blood%20transcriptome%20profiling%20reveals%20signatures%20of%20metformin%20and%20its%20therapeutic%20response&rft.jtitle=PloS%20one&rft.au=Ustinova,%20Monta&rft.date=2020-08-11&rft.volume=15&rft.issue=8&rft.spage=e0237400&rft.epage=e0237400&rft.pages=e0237400-e0237400&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0237400&rft_dat=%3Cgale_plos_%3EA632200668%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2432837023&rft_id=info:pmid/32780768&rft_galeid=A632200668&rft_doaj_id=oai_doaj_org_article_be10e303651a4c3cafadde5947f85354&rfr_iscdi=true |