{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:59Z","timestamp":1789448579576,"version":"build-2803163510"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Imeglimin is an oral hypoglycemic agent marketed in Japan that has shown glucose-lowering effects in Japanese patients with type 2 diabetes in TIMES trials. However, it is not well known whether imeglimin can affect diabetic kidney disease (DKD). To clarify this, we investigated the potential association between the effects of imeglimin and DKD using diabetic mice (DM) and cultured endothelial cells. Administration of imeglimin significantly lowered urinary albumin excretion in DKD but did not significantly affect blood glucose and glycated albumin. RNA sequencing analysis of the renal cortex indicated the upregulation of antioxidant, oxidative phosphorylation, and AMP-activated protein kinase (AMPK) signaling pathways and downregulation of inflammation, atherosclerosis, and reactive oxygen species. Additionally, imeglimin decreased the mRNA expression of\n                    <jats:italic>TNF-\u03b1<\/jats:italic>\n                    ,\n                    <jats:italic>F4\/80<\/jats:italic>\n                    , and\n                    <jats:italic>fibronectin<\/jats:italic>\n                    in the renal cortex of mice with DKD. In parallel with the findings that imeglimin reduced the protein expression of fibronectin in the renal cortex of mice with DKD, renal histological fibrosis was significantly increased in diabetic mice compared with non-diabetic mice (NDM), which was significantly reduced in mice receiving imeglimin. In an\n                    <jats:italic>in vitro<\/jats:italic>\n                    study, high glucose (HG) induced the mRNA expression of\n                    <jats:italic>Nlrp3<\/jats:italic>\n                    ,\n                    <jats:italic>Vcam-1<\/jats:italic>\n                    , and\n                    <jats:italic>NOX4<\/jats:italic>\n                    , which were downregulated by imeglimin. These results suggest that imeglimin could improve albuminuria by partially suppressing inflammatory and fibrotic markers in DKD.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1895272","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:27:27Z","timestamp":1789446447000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Imeglimin may improve albuminuria associated with partial suppression of inflammatory and fibrotic markers in diabetic kidney disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Yoshimi","family":"Muta","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Diabetes, Fukuoka University School of Medicine","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Yokomizo","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Fukuoka University School of Medicine","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takako","family":"Kawanami","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Fukuoka University School of Medicine","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuriko","family":"Hamaguchi","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dai","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Fukuoka University School of Medicine","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuko","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Fukuoka University School of Medicine","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Senda","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Fukuoka University School of Medicine","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Takashi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Fukuoka University School of Medicine","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohta","family":"Kodama","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiji","family":"Kawanami","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Fukuoka University School of Medicine","place":["Fukuoka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1093\/eurheartj\/ehab777","article-title":"Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis","volume":"43","author":"Agarwal","year":"2022","journal-title":"Eur. Heart J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.2215\/cjn.11491116","article-title":"Diabetic kidney disease: challenges, progress, and possibilities","volume":"12","author":"Alicic","year":"2017","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"155796","DOI":"10.1016\/j.metabol.2024.155796","article-title":"Imeglimin improves systemic metabolism by targeting brown adipose tissue and gut microbiota in obese model mice","volume":"153","author":"Awazawa","year":"2024","journal-title":"Metabolism"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1808","DOI":"10.1111\/jdi.70135","article-title":"Long-term safety and efficacy of imeglimin in Japanese individuals with type 2 diabetes and chronic kidney disease: a 52-week postmarketing clinical study (TWINKLE)","volume":"16","author":"Babazono","year":"2025","journal-title":"J. Diabetes Investig."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.2337\/diabetes.54.6.1615","article-title":"The pathobiology of diabetic complications: a unifying mechanism","volume":"54","author":"Brownlee","year":"2005","journal-title":"Diabetes"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e22938","DOI":"10.1096\/fj.202202013RR","article-title":"Single-cell RNA-seq with spatial transcriptomics to create an atlas of human diabetic kidney disease","volume":"37","author":"Chen","year":"2023","journal-title":"Faseb J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"952","DOI":"10.2337\/dc20-0763","article-title":"Efficacy and safety of imeglimin monotherapy Versus placebo in Japanese patients with type 2 diabetes (TIMES 1): a double-blind, randomized, placebo-controlled, parallel-group, multicenter phase 3 trial","volume":"44","author":"Dubourg","year":"2021","journal-title":"Diabetes Care"},{"key":"B8","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1111\/dom.14613","article-title":"Long-term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): a 52-week, open-label, multicentre phase 3 trial","volume":"24","author":"Dubourg","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e0241651","DOI":"10.1371\/journal.pone.0241651","article-title":"Imeglimin amplifies glucose-stimulated insulin release from diabetic islets via a distinct mechanism of action","volume":"16","author":"Hallakou-Bozec","year":"","journal-title":"PLoS One"},{"key":"B10","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1111\/dom.14277","article-title":"Mechanism of action of imeglimin: a novel therapeutic agent for type 2 diabetes","volume":"23","author":"Hallakou-Bozec","year":"","journal-title":"Diabetes Obes. Metab."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.3390\/antiox13111415","article-title":"Imeglimin halts liver damage by improving mitochondrial dysfunction in a nondiabetic Male mouse model of metabolic dysfunction-associated steatohepatitis","volume":"13","author":"Kaji","year":"2024","journal-title":"Antioxidants (Basel)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1111\/jdi.70092","article-title":"Imeglimin improves hyperglycemia and hypoglycemia-induced cell death and mitochondrial dysfunction in immortalized adult mouse schwann IMS32 cells","volume":"16","author":"Kato","year":"2025","journal-title":"J. Diabetes Investig."},{"key":"B13","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/s2213-8587(19)30249-9","article-title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials","volume":"7","author":"Kristensen","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e00128","DOI":"10.1002\/edm2.128","article-title":"Short-and long-term administration of imeglimin counters cardiorenal dysfunction in a rat model of metabolic syndrome","volume":"3","author":"Lachaux","year":"2020","journal-title":"Endocrinol. Diabetes Metab."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1007\/s40265-021-01589-9","article-title":"Imeglimin hydrochloride: first approval","volume":"81","author":"Lamb","year":"2021","journal-title":"Drugs"},{"key":"B16","doi-asserted-by":"publisher","first-page":"424","DOI":"10.2337\/db21-0123","article-title":"Imeglimin ameliorates \u03b2-Cell apoptosis by modulating the endoplasmic reticulum homeostasis pathway","volume":"71","author":"Li","year":"2022","journal-title":"Diabetes"},{"key":"B17","doi-asserted-by":"publisher","first-page":"116755","DOI":"10.1016\/j.biopha.2024.116755","article-title":"Exploring new mechanisms of imeglimin in diabetes treatment: amelioration of mitochondrial dysfunction","volume":"175","author":"Li","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B18","doi-asserted-by":"publisher","first-page":"156458","DOI":"10.1016\/j.metabol.2025.156458","article-title":"Imeglimin ameliorates MASLD by targeting PEN2 to activate AMPK pathway","volume":"175","author":"Li","year":"2026","journal-title":"Metabolism"},{"key":"B19","doi-asserted-by":"publisher","first-page":"603416","DOI":"10.3389\/fimmu.2021.603416","article-title":"Relevance of the pyroptosis-related inflammasome pathway in the pathogenesis of diabetic kidney disease","volume":"12","author":"Liu","year":"2021","journal-title":"Front. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"100382","DOI":"10.1016\/j.xkme.2021.08.016","article-title":"Race, income, and medical care spending patterns in high-risk primary care patients: results from the STOP-DKD (simultaneous risk factor control using telehealth to slow progression of diabetic kidney disease) study","volume":"4","author":"Machen","year":"2022","journal-title":"Kidney Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/nrd.2018.97","article-title":"Targeting the NLRP3 inflammasome in inflammatory diseases","volume":"17","author":"Mangan","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e165654","DOI":"10.1172\/jci165654","article-title":"Molecular pathways that drive diabetic kidney disease","volume":"133","author":"Mohandes","year":"2023","journal-title":"J. Clin. Invest"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3997","DOI":"10.1113\/jphysiol.2014.272328","article-title":"Diabetic kidney disease: from physiology to therapeutics","volume":"592","author":"Mora-Fern\u00e1ndez","year":"2014","journal-title":"J. Physiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1016\/s2213-8587(19)30256-6","article-title":"SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis","volume":"7","author":"Neuen","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1038\/s41591-019-0415-5","article-title":"A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes","volume":"25","author":"Niewczas","year":"2019","journal-title":"Nat. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1111\/jdi.70303","article-title":"Effects of imeglimin on experimental diabetic neuropathy in streptozotocin-induced diabetic rats","volume":"17","author":"Nihei","year":"2026","journal-title":"J. Diabetes Investig."},{"key":"B27","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.diabres.2017.03.024","article-title":"IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040","volume":"128","author":"Ogurtsova","year":"2017","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B28","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1042\/bcj20210700","article-title":"Differential effect of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice","volume":"479","author":"Otsuka","year":"2022","journal-title":"Biochem. J."},{"key":"B29","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1111\/dom.12452","article-title":"Imeglimin increases glucose-dependent insulin secretion and improves \u03b2-cell function in patients with type 2 diabetes","volume":"17","author":"Pacini","year":"2015","journal-title":"Diabetes Obes. Metab."},{"key":"B30","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.phrs.2016.11.004","article-title":"Roles of the NLRP3 inflammasome in the pathogenesis of diabetic nephropathy","volume":"114","author":"Qiu","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.kint.2022.10.030","article-title":"Targeting inflammation to treat diabetic kidney disease: the road to 2030","volume":"103","author":"Rayego-Mateos","year":"2023","journal-title":"Kidney Int."},{"key":"B32","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s12933-024-02189-z","article-title":"Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ","volume":"23","author":"Sanada","year":"2024","journal-title":"Cardiovasc Diabetol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1186\/s13098-025-01922-2","article-title":"Imeglimin as an effective therapeutic approach in management of type 2 diabetes mellitus: an umbrella review and systematic review, meta-regression and meta-analysis","volume":"17","author":"Song","year":"2025","journal-title":"Diabetol. Metab. Syndr."},{"key":"B34","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1038\/s41581-019-0234-4","article-title":"Innate immunity in diabetic kidney disease","volume":"16","author":"Tang","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e371","DOI":"10.1002\/edm2.371","article-title":"Phase 2 trial with imeglimin in patients with type 2 diabetes indicates effects on insulin secretion and sensitivity","volume":"5","author":"Theurey","year":"2022","journal-title":"Endocrinol. Diabetes Metab."},{"key":"B36","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.kint.2022.05.012","article-title":"Molecular mechanisms and therapeutic targets for diabetic kidney disease","volume":"102","author":"Tuttle","year":"2022","journal-title":"Kidney Int."},{"key":"B37","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1007\/s13300-023-01370-z","article-title":"Improving the effects of imeglimin on endothelial function: a prospective, single-center, observational study","volume":"14","author":"Uchida","year":"2023","journal-title":"Diabetes Ther."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2254","DOI":"10.2337\/db14-1220","article-title":"Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model","volume":"64","author":"Vial","year":"2015","journal-title":"Diabetes"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e00211","DOI":"10.1002\/edm2.211","article-title":"The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells","volume":"4","author":"Vial","year":"2021","journal-title":"Endocrinol. Diabetes Metab."},{"key":"B40","doi-asserted-by":"publisher","first-page":"100612","DOI":"10.1016\/j.conctc.2020.100612","article-title":"Lessons learned from two randomized controlled trials: CITIES and STOP-DKD","volume":"19","author":"Zullig","year":"2020","journal-title":"Contemp. Clin. Trials Commun."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1895272\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:27:28Z","timestamp":1789446448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1895272\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":40,"alternative-id":["10.3389\/fphar.2026.1895272"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1895272","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]},"article-number":"1895272"}}