{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T23:43:23Z","timestamp":1783035803470,"version":"3.54.6"},"reference-count":44,"publisher":"Georg Thieme Verlag KG","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Metab Res"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for the\n                    treatment of type 2 diabetes mellitus and heart failure. Its known ability to\n                    enhance mitochondrial adenosine triphosphate production and improve cardiac\n                    function led us to investigate whether blood adenosine triphosphate levels could\n                    serve as a predictive biomarker for treatment response. This prospective study\n                    included 120 patients from Kyrgyzstan: 49 with type 2 diabetes mellitus, 43 with\n                    heart failure, and 28 with both type 2 diabetes mellitus and heart failure. The\n                    mean age of the study population was 63.9\u00b17.1 years, with no significant age\n                    difference between groups. Patients received oral empagliflozin at a dose of\n                    either 10 or 25 mg daily for 12 weeks. Adenosine triphosphate activity was\n                    measured in erythrocytes from whole blood samples before and after treatment. In\n                    vitro assays were also performed, incubating patient blood samples with\n                    empagliflozin at concentrations of 0.1, 1, and 10 \u00b5M. In patients with type 2\n                    diabetes mellitus, empagliflozin significantly reduced body mass index\n                    (p=0.001), though HbA1c levels remained unchanged. Among heart failure\n                    patients, treatment resulted in a significant increase in left ventricular\n                    ejection fraction (p=0.028) and a decrease in B-type natriuretic peptide\n                    levels (p=0.01). Blood adenosine triphosphate concentrations increased\n                    significantly following empagliflozin treatment in both type 2 diabetes mellitus\n                    and heart failure groups. Proteomic analysis identified 12 differentially\n                    expressed proteins\u2014ADIPOQ, ARG1, CST3, CPPED1, GSTO1, FN1, ITIH4, LCN2, LCP1,\n                    MIF, PCMT1, and SERPINA3\u2014that are functionally linked to type 2 diabetes\n                    mellitus and\/or heart failure pathophysiology. Our data suggest that blood\n                    adenosine triphosphate activity may serve as a potential biomarker for clinical\n                    response to empagliflozin in patients with type 2 diabetes mellitus and heart\n                    failure. Further studies are warranted to validate these exploratory findings\n                    and to evaluate the sensitivity, specificity, and predictive value of blood\n                    adenosine triphosphate as a biomarker in these populations.<\/jats:p>","DOI":"10.1055\/a-2716-7109","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T23:53:08Z","timestamp":1763423588000},"page":"653-661","source":"Crossref","is-referenced-by-count":2,"title":["Proteomic Signatures and Blood Adenosine Triphosphate Levels as\n                    Markers of Empagliflozin Efficacy in Type 2 Diabetes Mellitus and Heart\n                    Failure"],"prefix":"10.1055","volume":"57","author":[{"given":"Uulkan","family":"Omurzakova","sequence":"additional","affiliation":[{"name":"Hospital Therapy, IK Akhunbaev Kyrgyz State Medical\n                    Academy, Faculty of General Medicine, Bishkek, Kyrgyzstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Breidert","sequence":"additional","affiliation":[{"name":"Gastroenterology, Kantonsspital Olten, Olten,\n                    Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Donner","sequence":"additional","affiliation":[{"name":"Gastroenterology, Kantonsspital Olten, Olten,\n                    Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8976-1636","authenticated-orcid":false,"given":"Nurgul","family":"Toktogulova","sequence":"additional","affiliation":[{"name":"Hospital Therapy, IK Akhunbaev Kyrgyz State Medical\n                    Academy, Faculty of General Medicine, Bishkek, Kyrgyzstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Moldobaeva","sequence":"additional","affiliation":[{"name":"Endocrinology, IK Akhunbaev Kyrgyz State Medical Academy, Faculty of\n                    General Medicine, KG, Bishkek, Kyrgyzstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9lique","family":"Quartier","sequence":"additional","affiliation":[{"name":"Inoviem Scientific, Illkirch-Graffenstaden,\n                    France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Eftekhari","sequence":"additional","affiliation":[{"name":"Inoviem Scientific, Illkirch-Graffenstaden,\n                    France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"ref1","volume-title":"Diabetes Atlas","year":"2025"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s12933-018-0728-6","article-title":"Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature\n                    review of scientific evidence from across the world in 2007-2017","volume":"17","author":"T R Einarson","year":"2018","journal-title":"Cardiovasc Diabetol"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1161\/CIRCULATIONAHA.114.014796","article-title":"REACH registry investigators. impact of diabetes mellitus on hospitalization for\n                    heart failure, cardiovascular events, and death: outcomes at 4 years from the\n                    reduction of atherothrombosis for continued health (REACH) registry","volume":"132","author":"M A Cavender","year":"2015","journal-title":"Circulation"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1161\/CIRCULATIONAHA.117.030012","article-title":"Sodium glucose cotransporter-2 inhibition in heart failure: potential\n                    mechanisms, clinical applications, and summary of clinical trials","volume":"136","author":"Y Lytvyn","year":"2017","journal-title":"Circulation"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"EMPA-REG OUTCOME investigators. empagliflozin, cardiovascular outcomes, and\n                    mortality in type 2 diabetes","volume":"373","author":"B Zinman","year":"2015","journal-title":"N Engl J Med"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1161\/CIRCULATIONAHA.120.052186","article-title":"Effect of empagliflozin on left ventricular volumes in patients with type 2\n                    diabetes, or prediabetes, and heart failure with reduced ejection fraction\n                    (SUGAR-DM-HF)","volume":"143","author":"MM Y Lee","year":"2021","journal-title":"Circulation"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1001\/jamacardio.2020.6827","article-title":"Associations of empagliflozin with left ventricular volumes, mass, and function\n                    in patients with heart failure and reduced ejection fraction: a substudy of the\n                    empire HF randomized clinical trial","volume":"6","author":"M Omar","year":"2021","journal-title":"JAMA Cardiol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.3390\/cells9112496","article-title":"Extracellular ATP: a feasible target for cancer therapy","volume":"9","author":"V Vultaggio-Poma","year":"2020","journal-title":"Cells"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12979-024-00441-4","article-title":"Impaired ATP hydrolysis in blood plasma contributes to age-related neutrophil\n                    dysfunction","volume":"21","author":"C Ledderose","year":"2024","journal-title":"Immun Ageing"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1161\/CIRCULATIONAHA.121.053575","article-title":"Altered cardiac energetics and mitochondrial dysfunction in hypertrophic\n                    cardiomyopathy","volume":"144","author":"S Ranjbarvaziri","year":"2021","journal-title":"Circulation"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"109333","DOI":"10.1016\/j.neuropharm.2022.109333","article-title":"Extracellular ATP: A powerful inflammatory mediator in the central nervous\n                    system","volume":"224","author":"F Di Virgilio","year":"2023","journal-title":"Neuropharmacology"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1161\/01.CIR.0000072789.89096.10","article-title":"Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2\n                    diabetes","volume":"107","author":"M Scheuermann-Freestone","year":"2003","journal-title":"Circulation"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1152\/ajpheart.00615.2024","article-title":"Cardiac energy metabolism in diabetes: emerging therapeutic targets and clinical\n                    implications","volume":"328","author":"A Panwar","year":"2025","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1194\/jlr.M400373-JLR200","article-title":"Adiponectin promotes adipocyte differentiation, insulin sensitivity and lipid\n                    accumulation","volume":"46","author":"Y Fu","year":"2005","journal-title":"J Lipid Res"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"18638","DOI":"10.1038\/s41598-024-69623-w","article-title":"Serum Cystatin C levels increase with increasing visceral fat area in patients\n                    with type 2 diabetes mellitus","volume":"14","author":"X Cong","year":"2024","journal-title":"Sci Rep"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"457","DOI":"10.5483\/BMBRep.2023-0038","article-title":"Inhibition of glutathione S-transferase omega 1-catalyzed protein\n                    deglutathionylation suppresses adipocyte differentiation","volume":"56","author":"S Iram","year":"2023","journal-title":"BMB Rep"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3390\/endocrines6010004","article-title":"Lipocalin 2 in obesity and diabetes: Insights into its role in energy\n                    metabolism","volume":"6","author":"E Lindstrom","year":"2025","journal-title":"Endocrines"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"106053","DOI":"10.1016\/j.biocel.2021.106053","article-title":"Loss of lymphocyte cytosolic protein 1 (LCP1) induces browning in 3T3-L1\n                    adipocytes via \u03b23-AR and the ERK-independent signaling pathway","volume":"138","author":"M Subramani","year":"2021","journal-title":"Int J Biochem Cell Biol"},{"issue":"17","key":"ref19","first-page":"3213","article-title":"Reduced cardiac muscle power with low ATP simulating heart failure","volume":"121","author":"D A Beard","year":"2022","journal-title":"Physiol J"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1038\/sj.bjp.0702214","article-title":"Evidence for two different types of P2 receptors stimulating insulin secretion\n                    from pancreatic B cell","volume":"125","author":"P Petit","year":"1998","journal-title":"Br J Pharmacol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1161\/CIRCRESAHA.121.318241","article-title":"Cardiac energy metabolism in heart failure","volume":"128","author":"G D Lopaschuk","year":"2021","journal-title":"Circ Res"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.jacc.2012.08.1021","article-title":"Mitochondria as a therapeutic target in heart failure","volume":"61","author":"M Bayeva","year":"2013","journal-title":"J Am Coll Cardiol"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1093\/cvr\/cvae231","article-title":"Advances in myocardial energy metabolism: metabolic remodelling in heart failure\n                    and beyond Open Access","volume":"120","author":"Q Sun","year":"2024","journal-title":"Cardiovasc Res"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.2337\/db21-0270","article-title":"Empagliflozin treatment is associated with improvements in cardiac energetics\n                    and function and reductions in myocardial cellular volume in patients with type\n                    2 diabetes","volume":"70","author":"S Thirunavukarasu","year":"2021","journal-title":"Diabetes"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"103010","DOI":"10.1016\/j.redox.2023.103010","article-title":"Empagliflozin improves mitochondrial dysfunction in diabetic cardiomyopathy by\n                    modulating ketone body metabolism and oxidative stress","volume":"69","author":"W Cai","year":"2024","journal-title":"Redox Biol"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1093\/cvr\/cvad157","article-title":"Empagliflozin improves cardiac energetics during ischaemia\/reperfusion by\n                    directly increasing cardiac ketone utilization","volume":"119","author":"D Chase","year":"2023","journal-title":"Cardiovasc Res"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1161\/CIRCULATIONAHA.122.062021","article-title":"Assessment of cardiac energy metabolism, function, and physiology in patients\n                    with heart failure taking empagliflozin: the randomized, controlled EMPA-VISION\n                    trial","volume":"147","author":"M J Hundertmark","year":"2023","journal-title":"Circulation"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"588","DOI":"10.3390\/biomedicines12030588","article-title":"Proteomic profiling of SGLT-2 inhibitor canagliflozin in a swine model of\n                    chronic myocardial ischemia","volume":"12","author":"D D Harris","year":"2024","journal-title":"Biomedicines"},{"key":"ref29","first-page":"575","article-title":"Empagliflozin increases cardiac energy production in diabetes: novel\n                    translational insights into the heart failure benefits of SGLT2 inhibitors","volume":"3","author":"S Verma","year":"2018","journal-title":"JACC Basic Transl Sci"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"339","DOI":"10.4093\/dmj.2019.0203","article-title":"Effect of dapagliflozin as an add-on therapy to insulin on the glycemic\n                    variability in subjects with type 2 diabetes mellitus (DIVE): A multicenter,\n                    placebo-controlled, double-blind, randomized study","volume":"45","author":"S H Lee","year":"2021","journal-title":"Diabetes Metab J"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3390\/life13112213","article-title":"Adiponectin: a promising target for the treatment of diabetes and its\n                    complications","volume":"13","author":"M Begum","year":"2023","journal-title":"Life"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1001\/jama.2009.976","article-title":"Adiponectin levels and risk of type 2 diabetes: a systematic review and\n                    meta-analysis","volume":"302","author":"S Li","year":"2009","journal-title":"JAMA"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.bbrc.2020.01.151","article-title":"GSTO1 regulates insulin biosynthesis in pancreatic \u03b2 cells","volume":"524","author":"L Wang","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1111\/j.1365-2796.2004.01414.x","article-title":"Serum cystatin C advantageous compared with serum creatinine in the detection of\n                    mild but not severe diabetic nephropathy","volume":"256","author":"A G Christensson","year":"2004","journal-title":"J Intern Med"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"35794","DOI":"10.1097\/MD.0000000000035794","article-title":"FN1 and TGFBI are key biomarkers of macrophage immune injury in diabetic kidney\n                    disease","volume":"102","author":"F Dou","year":"2023","journal-title":"Medicine."},{"key":"ref36","doi-asserted-by":"crossref","first-page":"638112","DOI":"10.3389\/fphys.2021.638112","article-title":"Lipocalin-2 in diabetic complications of the nervous system: physiology,\n                    pathology, and beyond","volume":"12","author":"A Bhusal","year":"2021","journal-title":"Front Physiol"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s42764-020-00014-x","article-title":"Lymphocyte cytosolic protein 1 (LCP1) is a novel TRAF3 dysregulation biomarker\n                    with potential prognostic value in multiple myeloma","volume":"1","author":"E M Shin","year":"2020","journal-title":"Genome Instab Dis"},{"key":"ref38","first-page":"119","article-title":"L-arginase induces vascular dysfunction in old spontaneously hypertensive\n                    rats","volume":"7","author":"O Arishe","year":"2019","journal-title":"J Afr Assoc Physiol Sci"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.4161\/15548627.2014.981789","article-title":"ARG2 impairs endothelial autophagy through regulation of MTOR and PRKAA\/AMPK\n                    signaling in advanced atherosclerosis","volume":"10","author":"Y Y Xiong","year":"2014","journal-title":"Autophagy"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/joim.12785","article-title":"Arginase inhibition improves endothelial function in patients with type 2\n                    diabetes mellitus despite intensive glucose-lowering therapy","volume":"284","author":"A Mahdi","year":"2018","journal-title":"J Intern Med"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1111\/joim.13358","article-title":"Arginase 1 is upregulated at admission in patients with ST-elevation myocardial\n                    infarction","volume":"290","author":"J Tengbom","year":"2021","journal-title":"J Intern Med"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1007\/s00421-011-2257-9","article-title":"Upregulation of arginase-II contributes to decreased age-related myocardial\n                    contractile reserve","volume":"112","author":"M Khan","year":"2012","journal-title":"Eur J Appl Physiol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.2217\/bmm-2022-0673","article-title":"Serum ITIH4 in coronary heart disease: a potential anti-inflammatory biomarker\n                    related to stenosis degree and risk of major adverse cardiovascular events","volume":"16","author":"Y Huo","year":"2022","journal-title":"Biomark Med"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"4780","DOI":"10.1002\/ehf2.13659","article-title":"Circulating SERPINA3 improves prognostic stratification in patients with a de\n                    novo or worsened heart failure","volume":"8","author":"L Delrue","year":"2021","journal-title":"ESC Heart Fail"}],"container-title":["Hormone and Metabolic Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2716-7109.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T23:46:22Z","timestamp":1763768782000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2716-7109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,21]]},"published-print":{"date-parts":[[2025,11]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2716-7109","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0018-5043","1439-4286"],"issn-type":[{"value":"0018-5043","type":"print"},{"value":"1439-4286","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11]]}}}